dalotuzumab (MK 0646) / Merck (MSD), Pierre Fabre - LARVOL DELTA

Recent Advances and Challenges in the Treatment of Advanced Pancreatic Cancer: An Update on Completed and Ongoing Clinical Trials. (PubMed, Cancers (Basel)) - "This includes adagrasib (a KRAS inhibitor), olaparib (a PARP inhibitor for BRCA mutations), APG-1387 (an IAP antagonist), minnelide (an anti-stromal agent), arimastat (an MMP inhibitor), MK-0646 (an IGF1R inhibitor), sirolimus (an mTOR inhibitor), and metabolic inhibitors. Furthermore, we have summarized novel approaches such as cancer vaccines and ablation techniques as emerging strategies in the treatment of advanced pancreatic cancer. We have also examined the challenges in treating advanced pancreatic cancer and the factors contributing to therapeutic failure, which may offer valuable insights for developing more effective treatment strategies and innovative drug designs."

Journal • Review • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • BRCA • KRAS

The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer: A Network Meta-Analysis. (PubMed, Eur J Pharmacol) - "In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected."

Journal • Retrospective data • Review • Colorectal Cancer • Oncology • Solid Tumor

Employing splice-switching oligonucleotides and AAVrh74.U7 snRNA to target insulin receptor splicing and cancer hallmarks in osteosarcoma. (PubMed, Mol Ther Oncol) - "After observing additive impacts on phosphoprotein phosphorylation and anoikis-resistant growth with the dalotuzumab and SSO combination, we treated OS cells with dalotuzumab and the AAVrh74.U7 snRNA IR virus, which significantly slowed OS cell proliferation. While these viruses require further optimization, we highlight the potential for SSO therapy and viral vector delivery, as it may offer new treatment avenues for OS patients and be translated to other cancers."

Journal • Gene Therapies • Oncology • Osteosarcoma • Pediatrics • Sarcoma • Solid Tumor • IR

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review. (PubMed, Front Pharmacol) - "Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy...These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes...Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus's clinical applications."

Journal • Review • Breast Cancer • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Trial of Fulvestrant, MK-0646, and Dasatinib for Metastatic Hormone Receptor-Positive HER2-Negative Breast Cancer (clinicaltrials.gov) - P1/2; N=11; Terminated; Sponsor: M.D. Anderson Cancer Center; N=40 ➔ 11

Clinical • Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Trial of Fulvestrant, MK-0646, and Dasatinib for Metastatic Hormone Receptor-Positive HER2-Negative Breast Cancer (clinicaltrials.gov) - P1/2; N=11; Terminated; Sponsor: M.D. Anderson Cancer Center; Active, not recruiting ➔ Terminated; Low Accrual

Clinical • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

MK-0646 and Gemcitabine +/- Erlotinib for Patients With Advanced Pancreatic Cancer (clinicaltrials.gov) - P2; N=81; Completed; Sponsor: M.D. Anderson Cancer Center; Active, not recruiting ➔ Completed; Trial completion date: Jun 2019 ➔ Sep 2020; Trial primary completion date: Dec 2014 ➔ Sep 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A randomized phase 2 study of the triplet combination of ridaforolimus (RIDA), dalotuzumab (DALO) and exemestane (EX) compared to the ridaforolimus, exemestane doublet in high proliferation, estrogen receptor positive (ER+) advanced breast cancer (SABCS-2013) - Abstract #OT2-6-13; P2, N=84; NCT01605396; Sponsor: MSD; “The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates...Accrual has been completed with results expected in May 2014.”

Anticipated P2 data • Clinical protocol • Breast Cancer • Oncology

[Poster coverage] A phase 2 study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer (SABCS-2013) - Abstract #P2-16-04; P2, N=66; "Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively."

P2 data • Breast Cancer • Oncology

Molecular analysis of the randomized phase II/III study of the anti-IGF-1R antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC) (ASCO 2012) - Presentation time: Friday June 1, 1:00 PM to 5:00 PM; P2/3, N=498; Study ID MK-0646-004; Within the pbo arm, high IGF-1 expression was found to be associated with resistance to Cx (IGF-1-/IGF-1+; PFS 6.7/3.7 mos, OS 15.5/9.6 mos); High IGF-1 expression was associated with benefit from the addition of weekly Dz (pbo/weekly Dz; PFS 3.7/5.7 mos, OS 9.6/18.2 mos); By contrast the addition of Dz was not effective in tumors with high IGF-2 expression (pbo/weekly Dz; PFS 8.4/2.7 mos)

P2/3 data • Oncology

Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis (AACR-NCI- EORTC 2011) - The development of inhibitors of the PI3K-AKT-mTOR & IGF1R axis

Review • Breast Cancer • Hematological Malignancies • Hepatocellular Cancer • Melanoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma

Trial of fulvestrant, MK-0646, and dasatinib for metastatic hormone receptor-positive HER2-negative breast cancer (clinicaltrials.gov) - P1/2, N=40; Recruiting; N=100 -> 40; Change: Enrollment criteria

Enrollment • Protocol • Breast Cancer • Oncology

Updated analysis of phase II study of the anti-IGF-1R antibody MK-0646 with gemcitabine +/- erlotinib for advanced pancreatic cancer (APC) (14th ESMO World Congress on Gastrointestinal Cancer) - P2, N=72; Study ID: 2007-0910; Median PFS of arms A (G + MK-0646), B (G + E + MK-0646) & C (G + E) were 5.5 mos, 3.0 mos & 2.0 mos, respectively (p=0.17); Median OS of A was 11.3 mos, B- 8.9 mos & C- 5.7 mos (p=0.44)

P2 data • Oncology • Pancreatic Cancer

MK-0646 and gemcitabine +/- erlotinib for patients with advanced pancreatic cancer (clinicaltrials.gov) - P1/2, N=100; Recruiting -> Active, not recruiting; Primary completion date: Nov 2012 -> Nov 2013

Completion date • Enrollment closed • Trial delayed • Oncology • Pancreatic Cancer

Molecular analysis of the randomized phase II/III study of the anti-IGF-1R antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC) (ASCO 2012) - Presentation time: Fri, Jun 1; 1:00 PM - 5:00 PM; Anticipated presentation at ASCO 2012

Anticipated P2/3 data • Oncology

The growth factor signature (GFS) as an intermediate biomarker of response for development of PI3K-pathway inhibitors in patients with breast cancer (MK-8669-050) (clinicaltrials.gov) - P1, N=48; Sponsor: Merck; Active, not recruiting -> Completed.

Trial completion • Breast Cancer • Oncology

A phase II trial of ridaforolimus and exemestane, compared to ridaforolimus, dalotuzumab and exemestane in participants with breast cancer (MK-8669-064 AM2) (clinicaltrials.gov) - P2, N=150; Not yet recruiting -> Recruiting

Enrollment open • Oncology

Activity of the anti-IGF-1R antibody dalotuzumab (MK-0646) in KRAS-mutant colorectal cancer: Preclinical and clinical data (ASCO 2012) - Presentation time: Monday June 4, 8:00 AM to 12:00 PM; In pre-clinical models, Dz was found to be effective in inhibiting IGF-1 mediated cellular growth; In colorectal cancer xenograft models high IGF-1 was found to identify a sub-set of Dz responsive tumours; Combination studies demonstrated that Irinotecan exposure resulted in the activation of IGF-1R and PI3K signaling pathways, representing a possible cellular survival mechanism

Preclinical-animal • Oncology

A study of ridaforolimus (MK-8669) in combination with dalotuzumab (MK-0646) compared to standard of care treatment in estrogen receptor positive breast cancer patients (MK-8669-041 AM3) (clinicaltrials.gov) - P2, N=352; Sponsor: Merck; Active, not recruiting; Completion date: Apr 2013 -> Jul 2013.

Trial completion date • Breast Cancer • Oncology

A study of dalotuzumab + MK-2206, dalotuzumab + MK-0752, and dalotuzumab + MK-8669 combination therapies in participants with advanced cancer (MK-0646-027 AM2) (clinicaltrials.gov) - P1, N=109; Recruiting; Completion date: Jun ’13 -> Apr ’14

Completion date • Trial delayed • Oncology

A study of dalotuzumab + MK-2206 and dalotuzumab + MK-0752 combination therapies in participants with advanced cancer (MK-0646-027 AM1) (clinicaltrials.gov) - P1, N=109; Recruiting; Trial arm: 6 → 4; N=78 → 109

Enrollment • Protocol • Oncology

Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer (Cancer Chemother Pharmacol) - P1, N=20; Sponsor: Merck; NCT00925015; “The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase.”

P1 data • Colorectal Cancer • Oncology

A phase II trial of ridaforolimus and exemestane, compared to ridaforolimus, dalotuzumab and exemestane in participants with breast cancer (MK-8669-064 AM2) (clinicaltrials.gov) - P2, N=150; Not yet recruiting; New P2 trial

New trial • Breast Cancer • Oncology

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours (Br J Cancer) - P1, N=47; NCT01243762; "Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles."

P1 data • Oncology

Rational molecularly targeted combinations: A parallel-arm phase I trial of the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor MK-0752, in patients with advan..... (ASCO 2012) - Presentation time: Saturday June 2, 1:15 PM to 5:15 PM; P1, N=30; Study ID 0646-027; In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash); RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly; In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting); RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly

P1 data • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer