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Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma

Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine... Background: Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. Methods: Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. Results: MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P =0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3–4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B). Conclusions: MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome. Trial registration: This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008. Keywords: MK-0646, Gemcitabine, Erlotinib, Advanced pancreatic adenocarcinoma * Correspondence: [email protected] Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 2 of 9 Background Methods Pancreatic cancer (PCA) is an aggressive disease with < Study design 1-year median overall survival (OS). Gemcitabine This study was an open-label single-institution three- provided a survival advantage over 5-fluorouracil for part clinical trial comprising a phase I dose escalation advanced disease stage [1]. Combination regimens cohort, a phase II randomization cohort, and a phase II including gemcitabine/nab-paclitaxel or 5-fluorouracil/ expansion cohort. leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) result In phase I, a 3 + 3 dose escalation design was used to in improved survival over single-agent gemcitabine. The determine the MK-0646 maximum tolerable dose (MTD) median overall survival (OS) and progression-free sur- in combination with G (gemcitabine) (arm A) or G + E vival (PFS) were 8.5 and 5.5 months in the gemcitabine/ (erlotinib) (arm B). Gemcitabine was administered at nab-paclitaxel group as compared to 6.7 and 3.7 months 1000 mg/m over 100 min on days 1, 8, and 15 of a 28- with single-agent gemcitabine group. Likewise, the me- day cycle, while erlotinib was administered orally at dian overall survival (OS) and progression-free survival 100 mg daily. MK-0646 was administered intravenously at (PFS) were 11.1 and 6.4 months in the FOLFIRINOX two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on group as compared to 6.8 and 3.3 months with days 1, 8, 15, and 22. The MTD (i.e., recommended phase gemcitabine alone [2, 3]. However, the course of aggres- II dose (RP2D)) was defined as the highest dose that sive disease is unlikely to be altered by cytotoxic drugs induced a dose-limiting toxicity (DLT) in < 2 patients alone, and addition of molecularly targeted agents is the among at least six patients. Patient enrollment in this focus of current investigations. phase was sequential, not randomized (Fig. 1a). Previous studies showed that epidermal growth factor In phase II, patients were randomized into three arms: receptor (EGFR) aberrations are common in PCA and A (G + MK), B (G + MK + E), and C (G + E), where the represent therapeutic targets [4]. Furthermore, the RP2D from phase I was used for arms A and B. The addition of erlotinib to gemcitabine resulted in a modest primary endpoint was progression-free survival (PFS). A survival improvement over single-agent gemcitabine [5]. Bayesian adaptive randomization design was used where However, the association between clinical response to the first 45 patients were equally randomized among the erlotinib and the presence of EGFR and KRAS mutations three arms. As the trial progressed and data accrued, the remains to be conclusively proven, and studies have randomization was planned in favor of the treatment yielded inconsistent results [6–9] However, tumors that arm with better PFS results. If at any point, the posterior respond to EGFR inhibitors may develop resistance, probability of a given arm being better than other two either due to mutant KRAS, development of secondary arms was less than 10%, that arm was suspended. A EGFR mutations, c-met amplification, or cross talk minimum of 45 and a maximum of 78 patients were between EGFR and insulin-like growth factor-I receptor planned for enrollment. (IGF-1R) pathways [10]. In the expansion phase, additional patients were Binding of IGF-1 to its receptor (IGF-1R) initiates enrolled to receive G + MK for correlative studies. downstream signals that activate PI3K/Akt/mTOR and Plasma and tissue levels of IGF-1 were measured for MEK/Erk pathways, which stimulate cellular prolifera- phase II patients to assess the correlation between IGF-1 tion and induce drug resistance [11]. Inhibition of IGF- expression and OS. This clinical trial (NCT00769483) 1R signaling enhanced the antitumor effect of gemcita- was approved by the Institutional Review Board, and all bine and cisplatin in PCA xenografts and ovarian cancer study participants signed an informed consent. cell lines, respectively [12, 13]. Furthermore, the addition of h7C10, anti-IGF-1R monoclonal antibody (mAB), to cetuximab, EGFR mAB, in A549 non-small cell lung Patient selection cancer (NSCLC) xenograft models of wild-type EGFR The eligibility criteria included treatment naïve metastatic and activated RAS mutation led to growth inhibition, PCA; age > 18 years; Eastern Cooperative Oncology unlike cetuximab alone [14]. Group (ECOG) ≤ 1; adequate organ function; had measur- MK-0646, humanized IGF-1 mAB, binds to IGF-1R. able disease as defined by the Response Evaluation Criteria This binding inhibits IGF-1R autophosphorylation and in Solid Tumor (RECIST) version 1.1; ≥ 6monthselapsed downstream signaling activation of PI3K/Akt/mTOR since completion of previous therapy; and patients who and MEK/Erk pathways, leading to inhibition of cellular enrolled in phase II cohorts were required to had biopsies proliferation [15]. Our study was planned before the for correlative studies. clinical trials of gemcitabine/nab-paclitaxel or FOLFIRI- We excluded patients who had prior systemic therapy, NOX. Our purpose was to determine safety, tolerability, had brain metastases, were pregnant or nursing, had un- and outcomes of MK-0646 with gemcitabine ± erlotinib controlled illness that would limit study compliance, and in advanced PCA. had another cancer, except treated basal or squamous cell Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 3 of 9 Fig. 1 Study design schemes. a Phase I dose escalation trial scheme. b Phase II randomization trial scheme skin carcinoma or cervical carcinoma in situ, or if patient Adverse Events v3.0. Each patient was evaluated for DLT had been disease-free for > 2 years. after the first cycle; DLT was defined as grade 4 (G4) neutropenia for ≥ 7 days, febrile neutropenia (≥ G3 Safety and efficacy assessments neutropenia of any duration with fever ≥ 38.5 °C), G4 All patients underwent a complete medical evaluation, thrombocytopenia, or ≥ G3 non-hematological toxicity with assessment of ECOG status, adverse events, and excluding hyperglycemia, skin rash, nausea, vomiting, or hematological and organ function laboratory analysis on a diarrhea, unless these occurred despite maximal prophy- weekly basis during the first 2 cycles and once every cycle laxis or treatment. For all G3/4 TEAE, treatment was thereafter unless the patient experienced treatment- withheld until the patient’s symptoms resolved or returned emergent adverse events (TEAE). Radiological assessment to G1. Any dose interruption for > 14 days because of of tumor response according to RECIST version 1.1 TEAE was considered DLT. criteria was performed every 2 cycles. Plasma and tissue IGF-1 assay Dose-limiting toxicity Blood samples were collected, anticoagulated, and centri- All toxic effects were graded according to the National fuged; then, IGF-1 was measured in plasma by Quantikine Cancer Institute’s Common Terminology Criteria for Human IGF-1 enzyme-linked immunosorbent assay Kit. Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 4 of 9 The expression of IGF-1 in tissue was assessed by using Table 1 Patients demographics and clinico-pathological characteristics for phase I and II enrolled pancreatic cancer reverse transcription reaction. Pre-amplification tech- patients (N = 75) niques were used to amplify targeted cDNA prior to quan- Enrolled patients (N = 75) (%) titative polymerase chain reaction analysis. The generated data were then analyzed using LightCycler 480 software. Age group Median (range) 62.8 (44–83) Statistical analysis < 60 27 (36%) Patient characteristics were summarized using median ≥ 60 48 (64%) (range) for continuous variables and frequency (percent- Sex age) for categorical variables. The probabilities of overall Male to female ratio 1.7:1 survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. OS was Female 28 (37.3%) defined as the time interval between start of treatment Male 47 (62.7%) and death date. Patients who were alive were censored Race at the last follow-up date. PFS was defined as the time White 61 (81.3%) interval between start of treatment and date of disease Black 4 (5.3%) progression or death. Patients who were alive and Hispanic 4 (5.3%) without disease progression were censored at the last follow-up date. Log-rank tests were used to assess the Asian 4 (5.3%) differences in OS and PFS between treatment arms. All Others 2 (2.7%) statistical analyses were conducted by using SAS version Tumor differentiation 9.2 (SAS Institute Inc.) and S plus software version 8 Moderate 22 (29.3%) (TIBCO Software, Inc). P value < 0.05 was considered Poor 23 (30.7%) significant. Unknown 30 (40%) Results ECOG Study participants 0 8 (10.7%) A total of 81 patients were enrolled over the three cohorts 1 67 (89.3%) between December 2008 and October 2013. In phase I, 22 Tumor location patients were enrolled but only 21 were treated, as one Head 22 (29.3%) patient withdrew consent and was never treated with the Body 32 (42.7%) study drug. For phase II randomization cohort, 50 patients were enrolled and 45 patients were evaluable for evalu- Tail 19 (25.3%) ation. Of the 5 non-evaluable patients, 1 patient did not Unknown 2 (2.7%) pass the screen and was never treated, 1 patient withdrew Site of metastasis consent after being randomized to G + E, and 3 patients Liver 61 (75.3%) were not randomized or treated. The remaining 45 Lung 10 (12.3%) patients were equally randomized among the three arms. Peritoneal 15 (18.5%) An additional 9 patients were enrolled in the expansion cohort and were treated with G + MK. Overall, 75 patients Others 4 (5.3%) were treated in phase I and II. Patients’ demographics and CA19-9 (U/ml) clinical characteristics are summarized in Table 1. Median (range) 58,159.1 (0.9–58,160) ≤ 35 12 (16%) Phase I dose escalation > 35 63 (84%) The first 3 patients were treated with G + MK 5 mg/kg Previous treatment (arm A, level I) and completed the first cycle without DLT. The next 3 patients were treated with the same De novo 69 (92%) regimen plus erlotinib (arm B, level I) without DLT. The Surgery 4 (4.9%) next 3 patients were treated with G + MK 10 mg/kg Chemotherapy 4 (4.9%) (arm A, level II) without DLT. However, when erlotinib was added to this regimen in the next 3 patients, 1/3 developed DLT in the form of G3 febrile neutropenia none of these 3 additional patients in arm A, level II, (arm B, level II). An additional 3 patients were enrolled developed DLT, 1/3 patients enrolled in arm B, level II, in arm A, level II, and another 3 in arm B, level II. While developed DLT that required treatment interruption for Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 5 of 9 > 14 days. Therefore, an additional 3 patients were en- phase I and 15 from phase II) with G + MK + E 5 mg/kg. rolled under arm B, level I, without DLT. Thus, MK-0646 The median number of administered cycles was 2 (range 10 mg/kg was declared to be the MTD in combination 1–12) for arm A and 2 (range 1–23) for arm B. Responses with gemcitabine and 5 mg/kg the MTD in combination to treatment for these patients are summarized in Fig. 2b. with G + E (Fig. 1b). The estimated median PFS for phase I and phase II patients combined was 2.1 months (95% CI 1.8–7.2) for Phase II randomization and expansion cohort arm A and 1.8 months (95% CI 1.8–5.1) for arm B. The The median number of cycles administered was 2 (range median OS was 10.3 months (95% CI 8.0–14.3) for arm A 1–11) in arm A, 2 (range 1–23) in arm B, and 2 (range and 6.8 months (95% CI 4.8–14.9) for arm B (Fig. 4a, b). 1–7) in arm C. Treatment response was evaluated for all In terms of subsequent therapies administered after phase II patients except for 1 patient who was treated first-line G + M or G + E, Additional file 1 shows that with G + MK. The responses are summarized in Fig. 2a. 53.3% of patients progressed on G + E received support- Among the 45 randomized patients, the estimated ive care alone as compared with 40% of G + MK group. median PFS was 1.8 months (95% confidence interval [CI] 1.8–9.7) for arm A, 1.8 months (95% CI 1.7–5.5) for arm B, and 1.9 months (95% CI 1.8–5.4) for arm C. The Treatment toxicity and tolerability difference between arms A and C was marginally signifi- Additional file 2 summarizes the reported G3/4 TEAE in cant (P = 0.09), but the difference between arms A and B phase II cohorts. The most frequently reported grade 3 was not significant (P = 0.20; Fig. 3a). Furthermore, the toxicity in group A were hyperglycemia (33.3%), median OS was 10.4 months (95% CI 3.9–18.9) for arm thrombocytopenia (29.2%), leukopenia (20.8%), A, 7.1 months (95% CI 5.2–20.0) for arm B, and 5. lymphopenia (20.8%), neutropenia (16.7%), and elevated 7 months (95% CI 4.0–9.5) for arm C. However, patients AST (12.5%); in group B, toxicities noted were treated with G + MK had a significantly longer OS than thrombocytopenia (53.3%), neutropenia (53.3%), patients treated with G + E (P = 0.02). Addition of erloti- leukopenia (33.3%), fatigue (26.7%), elevated ALT (20%), nib to G + MK did not improve OS (P = 0.60; Fig. 3b). hyponatremia (20%), and acne-like rash (13.3%); and in We also computed the posterior probability of each arm group C, they were neutropenia (33.3%), leukopenia (33. in terms of PFS, and the probability of G + E arm was 3%), anemia (13.3%), and fatigue (13.3%). Furthermore, below the pre-defined threshold of 0.10. We therefore 40% of patients treated in group B developed G4 neutro- withheld patient enrollment in G + E arm and expanded penia, compared to 25% in arm A. Generally, 3 patients enrollment to additional 9 patients for G + MK arm. in arm A and 4 patients in arm B developed a DLT, in During phase I and phase II combined, a total of 30 the form of G4 thrombocytopenia and G4 neutropenia patients (6 from phase I and 24 from phase II) were for ≥ 7 days. None of the patients developed febrile treated with G + MK 10 mg/kg and 21 patients (6 from neutropenia. Fig. 2 Treatment response within the treatment arms. a Treatment response rates between patients treated with gemcitabine + MK-0646, gemcitabine + MK-0646 + erlotinib, and gemcitabine + erlotinib alone as a part of phase II randomization cohort. b Treatment response rates for all patients treated with gemcitabine + MK-0646 (10 mg/kg) compared with gemcitabine + MK-0646 (5 mg/kg) + erlotinib as a part of phase I and II (randomization and expansion) cohorts. G, gemcitabine; M, MK-0646; E, erlotinib; PD, progressive disease; PR, partial response; SD, stable disease Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 6 of 9 Fig. 3 Kaplan-Meier curves for the three arms of the phase II randomization cohort. a Kaplan-Meier progression-free survival curves between the three arms of the phase II randomization cohort. b Kaplan-Meier overall survival curves between the three arms of the phase II randomization cohort. G, gemcitabine; M, MK-0646; E, erlotinib IGF-1 as a predictive marker for MK-0646 Notably, G + MK was associated with acceptable toxicity Among phase II cohorts, 21 patients had available and longer OS than G + E in the phase II. Furthermore, plasma and 23 patients had available tissue to measure addition of erlotinib to G + MK did not improve OS and the level of IGF-1. Although the mean level of plasma PFS. The observed adverse events associated with MK- IGF-1 was higher in patients with OS ≥ 12 months, there 0646 were generally tolerable, the most frequently re- was no significant correlation between plasma IGF-1 ported being hyperglycemia and hematological toxicities. level and OS (P = 0.64). The same result was noted for The IGF pathway is regulated by two ligands (IGF-1 the IGF-1 tissue expression (P = 0.87). However, the lack and IGF-1I), two transmembrane receptors (IGF-1R and of significant effects could be due to the small sample of IGF-1IR), and up to ten IGF-binding proteins (IGFBPs). patients with OS ≥ 12 months (Additional file 3). Binding of IGF-1 and IGF-1I to their receptors results in auto-activation of tyrosine kinases and autophosphoryl- Discussion ation of tyrosines, including tyrosine 950 in the juxta- Based on our phase I dose escalation results, we deter- membrane, which can serve as the docking site for the mined that MK-0646 RP2D is 10 mg/kg in combination insulin receptor substrates (IRS) and SHC. IRS-I stimu- with gemcitabine and 5 mg/kg in combination with G + E. lates the PI3K/AKT/mTOR, Src, and SHC pathways. Fig. 4 Kaplan-Meier curves for all patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib during phase I and II (randomization and expansion) cohorts. a Kaplan-Meier progression-free survival curves for patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib. b Kaplan-Meier overall survival curves for patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 7 of 9 Activation of the SHC pathway induces formation of the possible explanation for this discordance is that a greater Grb-2/son of sevenless complex, which activates the p21 number of patients with G + M received second-line Ras and Raf/MEK/Erk pathways, leading to cellular pro- therapy as compared with G + E. More patients in the G liferation [16]. + E arm transitioned to supportive care or hospice due We demonstrated that IRS-specific small interfering to deterioration in performance status. RNA inhibited activation of PI3K/AKT/mTOR in These findings highlight the need to identify IGF-1R transfected PCA cells [17]. Therefore, investigating the mAB response predictive biomarkers. A significant IGF pathway in cancer is crucial. MK-0646, a humanized correlation between circulating level of free IGF-1 and IGF-1 mAB, has been previously tested in several response to figitumumab was reported in patients with cancers [18–23]. To our knowledge, this is the first NSCLC [29]. Furthermore, high tissue expression of IGF- clinical trial to evaluate MK-0646 efficacy and safety in 1 was a surrogate biomarker for response to MK-0646 PCA patients. [26]. Atzori et al. evaluated the safety and tolerability of The efficacy of IGF-1R inhibitors in the clinical setting MK-0646 in patients with advanced solid tumors express- is unproven. Although a few advanced solid tumors have ing IGF-1R and found that, although MK-0646 was well responded to IGF-1R inhibitors, the majority showed no tolerated, most tumors did not respond to treatment evidence of improvement. In a trial of the IGF-1R mAB despite their IGF-1R expression [22]. In our study, there [IMC-A12] ± cetuximab in metastatic colorectal was no significant correlation between IGF-1 level and OS carcinomas (MCRC), 1/41 patients had a partial tumor rate; however, this could be due to the limited size. response (PR) with combined therapy, while no antitu- Our study has several limitations. First, it is a single mor activity was observed in the monotherapy arm [24]. institutional experience with a limited sample size in MK-0646 was tolerable in combination with cisplatin each treatment arm. Also, in our study we compared and etoposide in small cell lung cancer, but the clinical MK-0646 with gemcitabine ± erlotinib. Although, gemci- response was not meaningfully different from cisplatin tabine alone is currently used for advanced pancreatic and etoposide alone [23]. In contrast, 10/28 sarcoma cancer patients with ECOG PS of 2, at the current time, patients treated with figitumumab, another IGF-1R first-line regimens of choice for patients with good per- mAB, had stable disease (SD) or PR [25]. In our study, formance status include FOLFIRINOX and gemcitabine/ addition of MK-0646 to G ± E yielded 53 and 36% SD nab-paclitaxel. Despite these limitations, we hypothesize rates, respectively, compared to 27% in patients treated that the combination of MK-0646 with the above with G + E. combination regimens may result in favorable outcomes, Preclinical studies showed a promising effect of MK- given its low toxicity and overall impact on survival 0646 + cetuximab [14]. In a randomized phase II/III resulting from sequential therapies. Multicenter trials study evaluating the response to MK-0646 + cetuximab exploring MK-0646 with combination chemotherapy + irinotecan in MCRC, addition of MK-0646 did not regimens are warranted. improve OS or tumor response [21]. The same treat- ment combination in a phase I clinical trial in Japanese Conclusion MCRC patients showed that the triple combination is Although addition of MK-0646 to gemcitabine resulted well tolerated [19]. A randomized phase II/III study was in an OS improvement and tolerable toxicities as com- initiated in the same population to evaluate safety, pared with gemcitabine plus erlotinib, a greater fraction tolerability, and effectiveness of this triple combination, of patients receiving gemcitabine + MK-0646 received but the trial was terminated at the first interim analysis second-line therapies as compared with gemcitabine and because the triple combination yielded significantly erlotinib. Future clinical trials are necessary to identify shorter OS and PFS [26]. Similarly, addition of cixutu- the impact of MK-0646 addition to gemcitabine/nab- mumab, humanized IGF-1R mAB, to G + E did not paclitaxel and FOLFIRINOX. improve PFS or OS compared with G + E alone in PCA [27]. These findings support our data wherein the Additional files addition of erlotinib did not result in any improvement in OS or PFS as compared with G + MK. In contrast, Additional file 1: Table summary of various post-study treatment approaches. (DOCX 18 kb) the combination of ganitumab, humanized IGF-1R mAB, Additional file 2: The most commonly reported grade 3 and 4 toxicity with gemcitabine was tolerable and associated with a in patients treated with gemcitabine + MK-0646 versus gemcitabine + trend in OS improvement compared to gemcitabine erlotinib with and without MK-0646. (DOCX 21 kb) alone in PCA [28]. This was also noted in our study with Additional file 3: A box plot flow to identify variations in insulin like G + MK. Although we have demonstrated that G + M growth factor 1 expression in plasma and tissue between patients with overall survival rate ≥ 12 months versus those with short survival defined demonstrated an improved OS as compared with G + E, as < 12 month. (TIF 107 kb) the PFS was not different between these arms. One Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 8 of 9 Abbreviations 3. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay DLT: Dose-limiting toxicity; E: Erlotinib; ECOG: Eastern Cooperative Oncology T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in Group; EGFR: Epidermal growth factor receptor; G: Gemcitabine; IGF- pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 1R: Insulin-like growth factor-1 receptor; IGFBPs: Insulin-like growth factor 2013;369:1691–703. binding proteins; IRS: Insulin receptor substrates; mAB: Monoclonal antibody; 4. Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor MCRC: Metastatic colorectal carcinomas; MTD: Maximum tolerable dose; receptor in pancreatic cancer. Cancers. 2011;3:1513–26. NSCLC: Non-small cell lung cancer; OS: Overall survival; PCA: Pancreatic 5. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, cancer; PFS: Progression-free survival; PR: Partial response; RECIST: Response Murawa P, Walde D, Wolff RA, et al. Erlotinib plus gemcitabine compared Evaluation Criteria in Solid Tumor; RP2D: Recommended phase II dose; with gemcitabine alone in patients with advanced pancreatic cancer: a SD: Stable disease; TEAE: Treatment-emergent adverse events phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6. Acknowledgements 6. Kim ST, Lim DH, Jang K-T, Lim T, Lee J, Choi Y-L, Jang H-L, Yi JH, Baek KK, We would like to thank all participating patients and their families. Editorial Park SH, et al. Impact of KRAS mutations on clinical outcomes in pancreatic assistance was provided by Kathryn Hale from UT MD Anderson Scientific cancer patients treated with first-line gemcitabine-based chemotherapy. publication department. Mol Cancer Ther. 2011;10:1993–9. 7. Wang JP, Wu C-Y, Yeh Y-C, Shyr Y-M, Wu Y-Y, Kuo C-Y, Hung Y-P, Chen M-H, Lee W-P, Luo J-C, et al. Erlotinib is effective in pancreatic cancer with Funding epidermal growth factor receptor mutations: a randomized, open-label, This clinical trial was sponsored by Merck Sharp & Dohme Corp. and MD prospective trial. Oncotarget. 2015;6:18162–73. Anderson Cancer Center. 8. da Cunha SG, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS. Molecular predictors of outcome in a Availability of data and materials phase 3 study of gemcitabine and erlotinib therapy in patients with The datasets generated and/or analyzed during the current study are not advanced pancreatic cancer: National Cancer Institute of Canada Clinical publicly available due to patients’ confidentiality but are available from the Trials Group Study PA.3. Cancer. 2010;116:5599–607. corresponding author on reasonable request. 9. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, Heinemann V. KRAS mutation status is Authors’ contributions not predictive for objective response to anti-EGFR treatment with erlotinib Dr. MJ had full access to all of the data in the study takes responsibility for in patients with advanced pancreatic cancer. J Gastroenterol. 2013;48:544–8. the integrity and the accuracy of the data analysis. MJ contributed to the 10. Faller BA, Burtness B. Treatment of pancreatic cancer with epidermal growth study concept and design. RA, GRV, DRF, RTS, MJO, RAW, and MJ helped in factor receptor-targeted therapy. Biologics. 2009;3:419–28. the acquisition of data. RA and XW helped in the analysis and interpretation 11. Steelman LS, Chappell WH, Abrams SL, Kempf CR, Long J, Laidler P, of data. RA, GRV, PRB, XW, DRF, RTS, MJO, RAW, and MJ helped in drafting Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, et al. Roles of the manuscript. RA, GRV, PRB, XW, DRF, RTS, MJO, RAW, and MJ contributed the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling to the critical revision of the manuscript for important intellectual content. growth and sensitivity to therapy-implications for cancer and aging. RA and XW did the statistical analysis. MJ obtained funding; provided Aging (Albany NY). 2011;3:192–222. administrative, technical, or material support; and supervised the study. 12. Tian X, Hao K, Qin C, Xie K, Xie X, Yang Y. Insulin-like growth factor 1 All authors read and approved the final manuscript. receptor promotes the growth and chemoresistance of pancreatic cancer. Dig Dis Sci. 2013;58:2705–12. Ethics approval and consent to participate 13. Eckstein N, Servan K, Hildebrandt B, Pölitz A, Gv J, Wolf-Kümmeth S, This clinical trial (NCT00769483) was approved by the MD Anderson Napierski I, Hamacher A, Kassack MU, Budczies J, et al. Hyperactivation Institutional Review Board, and all study participants signed an informed of the insulin-like growth factor receptor I signaling pathway is an consent. essential event for cisplatin resistance of ovarian cancer cells. Cancer Res. 2009;69:2996–3003. Competing interests 14. Goetsch L, Gonzalez A, Leger O, Beck A, Pauwels PJ, Haeuw JF, Corvaia N. A The authors declare that they have no competing interests. recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti- epidermal growth factor receptor therapy against human cancer xenografts. Publisher’sNote Int J Cancer. 2005;113:316–28. Springer Nature remains neutral with regard to jurisdictional claims in 15. Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S. published maps and institutional affiliations. Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther. 2010;12:361–71. Author details 16. Abdel-Wahab R, Shehata S, Hassan MM, Habra MA, Eskandari G, Tinkey PT, Department of Gastrointestinal Medical Oncology, The University of Texas Mitchell J, Lee JS, Amin HM, Kaseb AO. Type I insulin-like growth factor as a MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX liver reserve assessment tool in hepatocellular carcinoma. J Hepatocell 77030, USA. Department of Diagnostic Radiology, The University of Texas Carcinoma. 2015;2:131–42. MD Anderson Cancer Center, Houston, TX, USA. Department of Biostatistics, 17. Dong X, Javle M, Hess KR, Shroff R, Abbruzzese JL, Li D. Insulin-like growth The University of Texas MD Anderson Cancer Center, Houston, TX, USA. factor axis gene polymorphisms and clinical outcomes in pancreatic cancer. Clinical Oncology Department, Assiut University Hospitals, Assiut, Egypt. Gastroenterology. 2010;139:464–73. 473.e461-463 18. Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Brana I, Received: 14 February 2018 Accepted: 6 May 2018 Roda D, Haines BB, Zhang T, Winter CG, et al. 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FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl 20. Reidy-Lagunes DL, Vakiani E, Segal MF, Hollywood EM, Tang LH, Solit DB, J Med. 2011;364:1817–25. Pietanza MC, Capanu M, Saltz LB. A phase 2 study of the insulin-like growth Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 9 of 9 factor-1 receptor inhibitor MK-0646 in patients with metastatic, well- differentiated neuroendocrine tumors. Cancer. 2012;118:4795–800. 21. Sclafani F, Kim TY, Cunningham D, Kim TW, Tabernero J, Schmoll HJ, Roh JK, Kim SY, Park YS, Guren TK, et al. A randomized phase II/III study of dalotuzumab in combination with cetuximab and irinotecan in chemorefractory, KRAS wild-type, metastatic colorectal cancer. J Natl Cancer Inst. 2015;107:djv258. 22. Atzori F, Tabernero J, Cervantes A, Prudkin L, Andreu J, Rodriguez-Braun E, Domingo A, Guijarro J, Gamez C, Rodon J, et al. 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Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma

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Copyright © 2018 by The Author(s).
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Medicine & Public Health; Oncology; Hematology; Cancer Research
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Abstract

Background: Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. Methods: Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. Results: MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P =0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3–4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B). Conclusions: MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome. Trial registration: This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008. Keywords: MK-0646, Gemcitabine, Erlotinib, Advanced pancreatic adenocarcinoma * Correspondence: [email protected] Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 2 of 9 Background Methods Pancreatic cancer (PCA) is an aggressive disease with < Study design 1-year median overall survival (OS). Gemcitabine This study was an open-label single-institution three- provided a survival advantage over 5-fluorouracil for part clinical trial comprising a phase I dose escalation advanced disease stage [1]. Combination regimens cohort, a phase II randomization cohort, and a phase II including gemcitabine/nab-paclitaxel or 5-fluorouracil/ expansion cohort. leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) result In phase I, a 3 + 3 dose escalation design was used to in improved survival over single-agent gemcitabine. The determine the MK-0646 maximum tolerable dose (MTD) median overall survival (OS) and progression-free sur- in combination with G (gemcitabine) (arm A) or G + E vival (PFS) were 8.5 and 5.5 months in the gemcitabine/ (erlotinib) (arm B). Gemcitabine was administered at nab-paclitaxel group as compared to 6.7 and 3.7 months 1000 mg/m over 100 min on days 1, 8, and 15 of a 28- with single-agent gemcitabine group. Likewise, the me- day cycle, while erlotinib was administered orally at dian overall survival (OS) and progression-free survival 100 mg daily. MK-0646 was administered intravenously at (PFS) were 11.1 and 6.4 months in the FOLFIRINOX two dose levels: 5 mg/kg (level I) or 10 mg/kg (level II) on group as compared to 6.8 and 3.3 months with days 1, 8, 15, and 22. The MTD (i.e., recommended phase gemcitabine alone [2, 3]. However, the course of aggres- II dose (RP2D)) was defined as the highest dose that sive disease is unlikely to be altered by cytotoxic drugs induced a dose-limiting toxicity (DLT) in < 2 patients alone, and addition of molecularly targeted agents is the among at least six patients. Patient enrollment in this focus of current investigations. phase was sequential, not randomized (Fig. 1a). Previous studies showed that epidermal growth factor In phase II, patients were randomized into three arms: receptor (EGFR) aberrations are common in PCA and A (G + MK), B (G + MK + E), and C (G + E), where the represent therapeutic targets [4]. Furthermore, the RP2D from phase I was used for arms A and B. The addition of erlotinib to gemcitabine resulted in a modest primary endpoint was progression-free survival (PFS). A survival improvement over single-agent gemcitabine [5]. Bayesian adaptive randomization design was used where However, the association between clinical response to the first 45 patients were equally randomized among the erlotinib and the presence of EGFR and KRAS mutations three arms. As the trial progressed and data accrued, the remains to be conclusively proven, and studies have randomization was planned in favor of the treatment yielded inconsistent results [6–9] However, tumors that arm with better PFS results. If at any point, the posterior respond to EGFR inhibitors may develop resistance, probability of a given arm being better than other two either due to mutant KRAS, development of secondary arms was less than 10%, that arm was suspended. A EGFR mutations, c-met amplification, or cross talk minimum of 45 and a maximum of 78 patients were between EGFR and insulin-like growth factor-I receptor planned for enrollment. (IGF-1R) pathways [10]. In the expansion phase, additional patients were Binding of IGF-1 to its receptor (IGF-1R) initiates enrolled to receive G + MK for correlative studies. downstream signals that activate PI3K/Akt/mTOR and Plasma and tissue levels of IGF-1 were measured for MEK/Erk pathways, which stimulate cellular prolifera- phase II patients to assess the correlation between IGF-1 tion and induce drug resistance [11]. Inhibition of IGF- expression and OS. This clinical trial (NCT00769483) 1R signaling enhanced the antitumor effect of gemcita- was approved by the Institutional Review Board, and all bine and cisplatin in PCA xenografts and ovarian cancer study participants signed an informed consent. cell lines, respectively [12, 13]. Furthermore, the addition of h7C10, anti-IGF-1R monoclonal antibody (mAB), to cetuximab, EGFR mAB, in A549 non-small cell lung Patient selection cancer (NSCLC) xenograft models of wild-type EGFR The eligibility criteria included treatment naïve metastatic and activated RAS mutation led to growth inhibition, PCA; age > 18 years; Eastern Cooperative Oncology unlike cetuximab alone [14]. Group (ECOG) ≤ 1; adequate organ function; had measur- MK-0646, humanized IGF-1 mAB, binds to IGF-1R. able disease as defined by the Response Evaluation Criteria This binding inhibits IGF-1R autophosphorylation and in Solid Tumor (RECIST) version 1.1; ≥ 6monthselapsed downstream signaling activation of PI3K/Akt/mTOR since completion of previous therapy; and patients who and MEK/Erk pathways, leading to inhibition of cellular enrolled in phase II cohorts were required to had biopsies proliferation [15]. Our study was planned before the for correlative studies. clinical trials of gemcitabine/nab-paclitaxel or FOLFIRI- We excluded patients who had prior systemic therapy, NOX. Our purpose was to determine safety, tolerability, had brain metastases, were pregnant or nursing, had un- and outcomes of MK-0646 with gemcitabine ± erlotinib controlled illness that would limit study compliance, and in advanced PCA. had another cancer, except treated basal or squamous cell Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 3 of 9 Fig. 1 Study design schemes. a Phase I dose escalation trial scheme. b Phase II randomization trial scheme skin carcinoma or cervical carcinoma in situ, or if patient Adverse Events v3.0. Each patient was evaluated for DLT had been disease-free for > 2 years. after the first cycle; DLT was defined as grade 4 (G4) neutropenia for ≥ 7 days, febrile neutropenia (≥ G3 Safety and efficacy assessments neutropenia of any duration with fever ≥ 38.5 °C), G4 All patients underwent a complete medical evaluation, thrombocytopenia, or ≥ G3 non-hematological toxicity with assessment of ECOG status, adverse events, and excluding hyperglycemia, skin rash, nausea, vomiting, or hematological and organ function laboratory analysis on a diarrhea, unless these occurred despite maximal prophy- weekly basis during the first 2 cycles and once every cycle laxis or treatment. For all G3/4 TEAE, treatment was thereafter unless the patient experienced treatment- withheld until the patient’s symptoms resolved or returned emergent adverse events (TEAE). Radiological assessment to G1. Any dose interruption for > 14 days because of of tumor response according to RECIST version 1.1 TEAE was considered DLT. criteria was performed every 2 cycles. Plasma and tissue IGF-1 assay Dose-limiting toxicity Blood samples were collected, anticoagulated, and centri- All toxic effects were graded according to the National fuged; then, IGF-1 was measured in plasma by Quantikine Cancer Institute’s Common Terminology Criteria for Human IGF-1 enzyme-linked immunosorbent assay Kit. Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 4 of 9 The expression of IGF-1 in tissue was assessed by using Table 1 Patients demographics and clinico-pathological characteristics for phase I and II enrolled pancreatic cancer reverse transcription reaction. Pre-amplification tech- patients (N = 75) niques were used to amplify targeted cDNA prior to quan- Enrolled patients (N = 75) (%) titative polymerase chain reaction analysis. The generated data were then analyzed using LightCycler 480 software. Age group Median (range) 62.8 (44–83) Statistical analysis < 60 27 (36%) Patient characteristics were summarized using median ≥ 60 48 (64%) (range) for continuous variables and frequency (percent- Sex age) for categorical variables. The probabilities of overall Male to female ratio 1.7:1 survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. OS was Female 28 (37.3%) defined as the time interval between start of treatment Male 47 (62.7%) and death date. Patients who were alive were censored Race at the last follow-up date. PFS was defined as the time White 61 (81.3%) interval between start of treatment and date of disease Black 4 (5.3%) progression or death. Patients who were alive and Hispanic 4 (5.3%) without disease progression were censored at the last follow-up date. Log-rank tests were used to assess the Asian 4 (5.3%) differences in OS and PFS between treatment arms. All Others 2 (2.7%) statistical analyses were conducted by using SAS version Tumor differentiation 9.2 (SAS Institute Inc.) and S plus software version 8 Moderate 22 (29.3%) (TIBCO Software, Inc). P value < 0.05 was considered Poor 23 (30.7%) significant. Unknown 30 (40%) Results ECOG Study participants 0 8 (10.7%) A total of 81 patients were enrolled over the three cohorts 1 67 (89.3%) between December 2008 and October 2013. In phase I, 22 Tumor location patients were enrolled but only 21 were treated, as one Head 22 (29.3%) patient withdrew consent and was never treated with the Body 32 (42.7%) study drug. For phase II randomization cohort, 50 patients were enrolled and 45 patients were evaluable for evalu- Tail 19 (25.3%) ation. Of the 5 non-evaluable patients, 1 patient did not Unknown 2 (2.7%) pass the screen and was never treated, 1 patient withdrew Site of metastasis consent after being randomized to G + E, and 3 patients Liver 61 (75.3%) were not randomized or treated. The remaining 45 Lung 10 (12.3%) patients were equally randomized among the three arms. Peritoneal 15 (18.5%) An additional 9 patients were enrolled in the expansion cohort and were treated with G + MK. Overall, 75 patients Others 4 (5.3%) were treated in phase I and II. Patients’ demographics and CA19-9 (U/ml) clinical characteristics are summarized in Table 1. Median (range) 58,159.1 (0.9–58,160) ≤ 35 12 (16%) Phase I dose escalation > 35 63 (84%) The first 3 patients were treated with G + MK 5 mg/kg Previous treatment (arm A, level I) and completed the first cycle without DLT. The next 3 patients were treated with the same De novo 69 (92%) regimen plus erlotinib (arm B, level I) without DLT. The Surgery 4 (4.9%) next 3 patients were treated with G + MK 10 mg/kg Chemotherapy 4 (4.9%) (arm A, level II) without DLT. However, when erlotinib was added to this regimen in the next 3 patients, 1/3 developed DLT in the form of G3 febrile neutropenia none of these 3 additional patients in arm A, level II, (arm B, level II). An additional 3 patients were enrolled developed DLT, 1/3 patients enrolled in arm B, level II, in arm A, level II, and another 3 in arm B, level II. While developed DLT that required treatment interruption for Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 5 of 9 > 14 days. Therefore, an additional 3 patients were en- phase I and 15 from phase II) with G + MK + E 5 mg/kg. rolled under arm B, level I, without DLT. Thus, MK-0646 The median number of administered cycles was 2 (range 10 mg/kg was declared to be the MTD in combination 1–12) for arm A and 2 (range 1–23) for arm B. Responses with gemcitabine and 5 mg/kg the MTD in combination to treatment for these patients are summarized in Fig. 2b. with G + E (Fig. 1b). The estimated median PFS for phase I and phase II patients combined was 2.1 months (95% CI 1.8–7.2) for Phase II randomization and expansion cohort arm A and 1.8 months (95% CI 1.8–5.1) for arm B. The The median number of cycles administered was 2 (range median OS was 10.3 months (95% CI 8.0–14.3) for arm A 1–11) in arm A, 2 (range 1–23) in arm B, and 2 (range and 6.8 months (95% CI 4.8–14.9) for arm B (Fig. 4a, b). 1–7) in arm C. Treatment response was evaluated for all In terms of subsequent therapies administered after phase II patients except for 1 patient who was treated first-line G + M or G + E, Additional file 1 shows that with G + MK. The responses are summarized in Fig. 2a. 53.3% of patients progressed on G + E received support- Among the 45 randomized patients, the estimated ive care alone as compared with 40% of G + MK group. median PFS was 1.8 months (95% confidence interval [CI] 1.8–9.7) for arm A, 1.8 months (95% CI 1.7–5.5) for arm B, and 1.9 months (95% CI 1.8–5.4) for arm C. The Treatment toxicity and tolerability difference between arms A and C was marginally signifi- Additional file 2 summarizes the reported G3/4 TEAE in cant (P = 0.09), but the difference between arms A and B phase II cohorts. The most frequently reported grade 3 was not significant (P = 0.20; Fig. 3a). Furthermore, the toxicity in group A were hyperglycemia (33.3%), median OS was 10.4 months (95% CI 3.9–18.9) for arm thrombocytopenia (29.2%), leukopenia (20.8%), A, 7.1 months (95% CI 5.2–20.0) for arm B, and 5. lymphopenia (20.8%), neutropenia (16.7%), and elevated 7 months (95% CI 4.0–9.5) for arm C. However, patients AST (12.5%); in group B, toxicities noted were treated with G + MK had a significantly longer OS than thrombocytopenia (53.3%), neutropenia (53.3%), patients treated with G + E (P = 0.02). Addition of erloti- leukopenia (33.3%), fatigue (26.7%), elevated ALT (20%), nib to G + MK did not improve OS (P = 0.60; Fig. 3b). hyponatremia (20%), and acne-like rash (13.3%); and in We also computed the posterior probability of each arm group C, they were neutropenia (33.3%), leukopenia (33. in terms of PFS, and the probability of G + E arm was 3%), anemia (13.3%), and fatigue (13.3%). Furthermore, below the pre-defined threshold of 0.10. We therefore 40% of patients treated in group B developed G4 neutro- withheld patient enrollment in G + E arm and expanded penia, compared to 25% in arm A. Generally, 3 patients enrollment to additional 9 patients for G + MK arm. in arm A and 4 patients in arm B developed a DLT, in During phase I and phase II combined, a total of 30 the form of G4 thrombocytopenia and G4 neutropenia patients (6 from phase I and 24 from phase II) were for ≥ 7 days. None of the patients developed febrile treated with G + MK 10 mg/kg and 21 patients (6 from neutropenia. Fig. 2 Treatment response within the treatment arms. a Treatment response rates between patients treated with gemcitabine + MK-0646, gemcitabine + MK-0646 + erlotinib, and gemcitabine + erlotinib alone as a part of phase II randomization cohort. b Treatment response rates for all patients treated with gemcitabine + MK-0646 (10 mg/kg) compared with gemcitabine + MK-0646 (5 mg/kg) + erlotinib as a part of phase I and II (randomization and expansion) cohorts. G, gemcitabine; M, MK-0646; E, erlotinib; PD, progressive disease; PR, partial response; SD, stable disease Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 6 of 9 Fig. 3 Kaplan-Meier curves for the three arms of the phase II randomization cohort. a Kaplan-Meier progression-free survival curves between the three arms of the phase II randomization cohort. b Kaplan-Meier overall survival curves between the three arms of the phase II randomization cohort. G, gemcitabine; M, MK-0646; E, erlotinib IGF-1 as a predictive marker for MK-0646 Notably, G + MK was associated with acceptable toxicity Among phase II cohorts, 21 patients had available and longer OS than G + E in the phase II. Furthermore, plasma and 23 patients had available tissue to measure addition of erlotinib to G + MK did not improve OS and the level of IGF-1. Although the mean level of plasma PFS. The observed adverse events associated with MK- IGF-1 was higher in patients with OS ≥ 12 months, there 0646 were generally tolerable, the most frequently re- was no significant correlation between plasma IGF-1 ported being hyperglycemia and hematological toxicities. level and OS (P = 0.64). The same result was noted for The IGF pathway is regulated by two ligands (IGF-1 the IGF-1 tissue expression (P = 0.87). However, the lack and IGF-1I), two transmembrane receptors (IGF-1R and of significant effects could be due to the small sample of IGF-1IR), and up to ten IGF-binding proteins (IGFBPs). patients with OS ≥ 12 months (Additional file 3). Binding of IGF-1 and IGF-1I to their receptors results in auto-activation of tyrosine kinases and autophosphoryl- Discussion ation of tyrosines, including tyrosine 950 in the juxta- Based on our phase I dose escalation results, we deter- membrane, which can serve as the docking site for the mined that MK-0646 RP2D is 10 mg/kg in combination insulin receptor substrates (IRS) and SHC. IRS-I stimu- with gemcitabine and 5 mg/kg in combination with G + E. lates the PI3K/AKT/mTOR, Src, and SHC pathways. Fig. 4 Kaplan-Meier curves for all patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib during phase I and II (randomization and expansion) cohorts. a Kaplan-Meier progression-free survival curves for patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib. b Kaplan-Meier overall survival curves for patients treated with gemcitabine + MK-0646 compared with gemcitabine + MK-0646 + erlotinib Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 7 of 9 Activation of the SHC pathway induces formation of the possible explanation for this discordance is that a greater Grb-2/son of sevenless complex, which activates the p21 number of patients with G + M received second-line Ras and Raf/MEK/Erk pathways, leading to cellular pro- therapy as compared with G + E. More patients in the G liferation [16]. + E arm transitioned to supportive care or hospice due We demonstrated that IRS-specific small interfering to deterioration in performance status. RNA inhibited activation of PI3K/AKT/mTOR in These findings highlight the need to identify IGF-1R transfected PCA cells [17]. Therefore, investigating the mAB response predictive biomarkers. A significant IGF pathway in cancer is crucial. MK-0646, a humanized correlation between circulating level of free IGF-1 and IGF-1 mAB, has been previously tested in several response to figitumumab was reported in patients with cancers [18–23]. To our knowledge, this is the first NSCLC [29]. Furthermore, high tissue expression of IGF- clinical trial to evaluate MK-0646 efficacy and safety in 1 was a surrogate biomarker for response to MK-0646 PCA patients. [26]. Atzori et al. evaluated the safety and tolerability of The efficacy of IGF-1R inhibitors in the clinical setting MK-0646 in patients with advanced solid tumors express- is unproven. Although a few advanced solid tumors have ing IGF-1R and found that, although MK-0646 was well responded to IGF-1R inhibitors, the majority showed no tolerated, most tumors did not respond to treatment evidence of improvement. In a trial of the IGF-1R mAB despite their IGF-1R expression [22]. In our study, there [IMC-A12] ± cetuximab in metastatic colorectal was no significant correlation between IGF-1 level and OS carcinomas (MCRC), 1/41 patients had a partial tumor rate; however, this could be due to the limited size. response (PR) with combined therapy, while no antitu- Our study has several limitations. First, it is a single mor activity was observed in the monotherapy arm [24]. institutional experience with a limited sample size in MK-0646 was tolerable in combination with cisplatin each treatment arm. Also, in our study we compared and etoposide in small cell lung cancer, but the clinical MK-0646 with gemcitabine ± erlotinib. Although, gemci- response was not meaningfully different from cisplatin tabine alone is currently used for advanced pancreatic and etoposide alone [23]. In contrast, 10/28 sarcoma cancer patients with ECOG PS of 2, at the current time, patients treated with figitumumab, another IGF-1R first-line regimens of choice for patients with good per- mAB, had stable disease (SD) or PR [25]. In our study, formance status include FOLFIRINOX and gemcitabine/ addition of MK-0646 to G ± E yielded 53 and 36% SD nab-paclitaxel. Despite these limitations, we hypothesize rates, respectively, compared to 27% in patients treated that the combination of MK-0646 with the above with G + E. combination regimens may result in favorable outcomes, Preclinical studies showed a promising effect of MK- given its low toxicity and overall impact on survival 0646 + cetuximab [14]. In a randomized phase II/III resulting from sequential therapies. Multicenter trials study evaluating the response to MK-0646 + cetuximab exploring MK-0646 with combination chemotherapy + irinotecan in MCRC, addition of MK-0646 did not regimens are warranted. improve OS or tumor response [21]. The same treat- ment combination in a phase I clinical trial in Japanese Conclusion MCRC patients showed that the triple combination is Although addition of MK-0646 to gemcitabine resulted well tolerated [19]. A randomized phase II/III study was in an OS improvement and tolerable toxicities as com- initiated in the same population to evaluate safety, pared with gemcitabine plus erlotinib, a greater fraction tolerability, and effectiveness of this triple combination, of patients receiving gemcitabine + MK-0646 received but the trial was terminated at the first interim analysis second-line therapies as compared with gemcitabine and because the triple combination yielded significantly erlotinib. Future clinical trials are necessary to identify shorter OS and PFS [26]. Similarly, addition of cixutu- the impact of MK-0646 addition to gemcitabine/nab- mumab, humanized IGF-1R mAB, to G + E did not paclitaxel and FOLFIRINOX. improve PFS or OS compared with G + E alone in PCA [27]. These findings support our data wherein the Additional files addition of erlotinib did not result in any improvement in OS or PFS as compared with G + MK. In contrast, Additional file 1: Table summary of various post-study treatment approaches. (DOCX 18 kb) the combination of ganitumab, humanized IGF-1R mAB, Additional file 2: The most commonly reported grade 3 and 4 toxicity with gemcitabine was tolerable and associated with a in patients treated with gemcitabine + MK-0646 versus gemcitabine + trend in OS improvement compared to gemcitabine erlotinib with and without MK-0646. (DOCX 21 kb) alone in PCA [28]. This was also noted in our study with Additional file 3: A box plot flow to identify variations in insulin like G + MK. Although we have demonstrated that G + M growth factor 1 expression in plasma and tissue between patients with overall survival rate ≥ 12 months versus those with short survival defined demonstrated an improved OS as compared with G + E, as < 12 month. (TIF 107 kb) the PFS was not different between these arms. One Abdel-Wahab et al. Journal of Hematology & Oncology (2018) 11:71 Page 8 of 9 Abbreviations 3. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay DLT: Dose-limiting toxicity; E: Erlotinib; ECOG: Eastern Cooperative Oncology T, Tjulandin SA, Ma WW, Saleh MN, et al. Increased survival in Group; EGFR: Epidermal growth factor receptor; G: Gemcitabine; IGF- pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 1R: Insulin-like growth factor-1 receptor; IGFBPs: Insulin-like growth factor 2013;369:1691–703. binding proteins; IRS: Insulin receptor substrates; mAB: Monoclonal antibody; 4. Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor MCRC: Metastatic colorectal carcinomas; MTD: Maximum tolerable dose; receptor in pancreatic cancer. Cancers. 2011;3:1513–26. NSCLC: Non-small cell lung cancer; OS: Overall survival; PCA: Pancreatic 5. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, cancer; PFS: Progression-free survival; PR: Partial response; RECIST: Response Murawa P, Walde D, Wolff RA, et al. Erlotinib plus gemcitabine compared Evaluation Criteria in Solid Tumor; RP2D: Recommended phase II dose; with gemcitabine alone in patients with advanced pancreatic cancer: a SD: Stable disease; TEAE: Treatment-emergent adverse events phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6. Acknowledgements 6. Kim ST, Lim DH, Jang K-T, Lim T, Lee J, Choi Y-L, Jang H-L, Yi JH, Baek KK, We would like to thank all participating patients and their families. Editorial Park SH, et al. Impact of KRAS mutations on clinical outcomes in pancreatic assistance was provided by Kathryn Hale from UT MD Anderson Scientific cancer patients treated with first-line gemcitabine-based chemotherapy. publication department. Mol Cancer Ther. 2011;10:1993–9. 7. Wang JP, Wu C-Y, Yeh Y-C, Shyr Y-M, Wu Y-Y, Kuo C-Y, Hung Y-P, Chen M-H, Lee W-P, Luo J-C, et al. Erlotinib is effective in pancreatic cancer with Funding epidermal growth factor receptor mutations: a randomized, open-label, This clinical trial was sponsored by Merck Sharp & Dohme Corp. and MD prospective trial. Oncotarget. 2015;6:18162–73. Anderson Cancer Center. 8. da Cunha SG, Dhani N, Tu D, Chin K, Ludkovski O, Kamel-Reid S, Squire J, Parulekar W, Moore MJ, Tsao MS. Molecular predictors of outcome in a Availability of data and materials phase 3 study of gemcitabine and erlotinib therapy in patients with The datasets generated and/or analyzed during the current study are not advanced pancreatic cancer: National Cancer Institute of Canada Clinical publicly available due to patients’ confidentiality but are available from the Trials Group Study PA.3. Cancer. 2010;116:5599–607. corresponding author on reasonable request. 9. Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Ormanns S, Haas M, Modest DP, Kirchner T, Heinemann V. KRAS mutation status is Authors’ contributions not predictive for objective response to anti-EGFR treatment with erlotinib Dr. MJ had full access to all of the data in the study takes responsibility for in patients with advanced pancreatic cancer. J Gastroenterol. 2013;48:544–8. the integrity and the accuracy of the data analysis. MJ contributed to the 10. Faller BA, Burtness B. Treatment of pancreatic cancer with epidermal growth study concept and design. RA, GRV, DRF, RTS, MJO, RAW, and MJ helped in factor receptor-targeted therapy. Biologics. 2009;3:419–28. the acquisition of data. RA and XW helped in the analysis and interpretation 11. Steelman LS, Chappell WH, Abrams SL, Kempf CR, Long J, Laidler P, of data. RA, GRV, PRB, XW, DRF, RTS, MJO, RAW, and MJ helped in drafting Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, et al. Roles of the manuscript. RA, GRV, PRB, XW, DRF, RTS, MJO, RAW, and MJ contributed the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling to the critical revision of the manuscript for important intellectual content. growth and sensitivity to therapy-implications for cancer and aging. RA and XW did the statistical analysis. MJ obtained funding; provided Aging (Albany NY). 2011;3:192–222. administrative, technical, or material support; and supervised the study. 12. Tian X, Hao K, Qin C, Xie K, Xie X, Yang Y. Insulin-like growth factor 1 All authors read and approved the final manuscript. receptor promotes the growth and chemoresistance of pancreatic cancer. Dig Dis Sci. 2013;58:2705–12. Ethics approval and consent to participate 13. Eckstein N, Servan K, Hildebrandt B, Pölitz A, Gv J, Wolf-Kümmeth S, This clinical trial (NCT00769483) was approved by the MD Anderson Napierski I, Hamacher A, Kassack MU, Budczies J, et al. Hyperactivation Institutional Review Board, and all study participants signed an informed of the insulin-like growth factor receptor I signaling pathway is an consent. essential event for cisplatin resistance of ovarian cancer cells. Cancer Res. 2009;69:2996–3003. Competing interests 14. Goetsch L, Gonzalez A, Leger O, Beck A, Pauwels PJ, Haeuw JF, Corvaia N. 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Type I insulin-like growth factor as a MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX liver reserve assessment tool in hepatocellular carcinoma. J Hepatocell 77030, USA. Department of Diagnostic Radiology, The University of Texas Carcinoma. 2015;2:131–42. MD Anderson Cancer Center, Houston, TX, USA. Department of Biostatistics, 17. Dong X, Javle M, Hess KR, Shroff R, Abbruzzese JL, Li D. Insulin-like growth The University of Texas MD Anderson Cancer Center, Houston, TX, USA. factor axis gene polymorphisms and clinical outcomes in pancreatic cancer. Clinical Oncology Department, Assiut University Hospitals, Assiut, Egypt. Gastroenterology. 2010;139:464–73. 473.e461-463 18. Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Brana I, Received: 14 February 2018 Accepted: 6 May 2018 Roda D, Haines BB, Zhang T, Winter CG, et al. 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Published: May 30, 2018

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