ganitumab (AMG 479)

P3, N=312, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

P1/2, N=138, Completed, NantCell, Inc. | Phase classification: P1b/2 --> P1/2

We report that low IGFBP7 gene expression identifies a subset of breast cancers for which the addition of ganitumab, an anti-IGF-1R monoclonal antibody, to neoadjuvant chemotherapy, substantially improved the pathological complete response rate compared to neoadjuvant chemotherapy alone...Furthermore, high IGFBP7 expression predicted increased distant metastasis risk. If our findings are confirmed, decisions to halt the development of IGF-1R targeting drugs, which were based on disappointing results of prior trials that did not use predictive biomarkers, should be reviewed.

P1/2, N=15, Terminated, NantCell, Inc. | Phase classification: P1b/2 --> P1/2 | N=49 --> 15

P1/2, N=213, Terminated, NantCell, Inc. | Phase classification: P1b/2 --> P1/2 | Completed --> Terminated; Subjects discontinued study

P1/2, N=89, Terminated, NantCell, Inc. | Phase classification: P1b/2 --> P1/2

P1/2, N=177, Completed, NantBioScience, Inc. | Phase classification: P1b/2 --> P1/2

P2, N=10, Terminated, Dana-Farber Cancer Institute | Completed --> Terminated; The study closed early due to discontinuation of ganitumab supply.

P3, N=800, Completed, NantCell, Inc. | Terminated --> Completed

P1, N=20, Not yet recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every two weeks was safe and tolerable. This combination had a disease control rate of 22% at five months.

This combination lacks adequate therapeutic activity for further study, though a subset of patients had prolonged stable disease.

IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

P2, N=10, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | N=18 --> 10

We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models.

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Aug 2022 --> Dec 2022

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2022 --> Dec 2022 | Trial primary completion date: Mar 2022 --> Aug 2022

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Oct 2021 --> Mar 2022

Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

P2, N=18, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

P2; Trial completion date: Dec 2026 --> Dec 2031 | Trial primary completion date: Dec 2025 --> Dec 2030

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P1 --> P2

P1/2, N=77, Terminated, Pfizer | Phase classification: P2 --> P1/2

P1, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P2 --> P1

PGM followed by doxorubicin/cyclophosphamide (AC) did not result in substantial increases in pCR when compared to P followed by AC. While IGF gene expression profiling associated with treatment response, they were not specific for PGM. Further, biomarker analysis and strategies to control glucose will be needed to optimize anti-IGF-1R therapies.

We demonstrate that combined trametinib and ganitumab treatment shows therapeutic synergy across a wide panel of RAS-mutated RMS preclinical models. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated RMS.

We demonstrate that combined trametinib and ganitumab treatment shows therapeutic synergy across a wide panel of RAS-mutated RMS preclinical models. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated RMS.

Regorafenib combined with chemotherapy might be a potential alternative to conventional therapeutic options in second-line treatment of patients with metastatic colorectal cancer and could be considered as the best option for treating patients with KRAS and BRAF mutated mCRC. However future RCTs are needed to confirm these results.

ctDNA levels will be measured using next generation sequencing for quantification of ctDNA and association with response, and for identification of genomic and epigenetic markers of resistance. Enrollment began in December 2019.

Our study involves 986 patients with pre treatment gene expression and pCR data across 10 treatment arms including inhibitors of HER2: neratinib (N), pertuzumab (P), TDM1/P; AKT (MK 2206; M); IGF1R (ganitumab); HSP90 (ganetespib); PARP/DNA repair (veliparib/carboplatin; VC); ANG 1/2 (AMG386); immune checkpoints (pembrolizumab; Pembro); and a shared control arm (Ctr). Our results suggests that hypothesis driven analysis restricted to assumed mechanisms of action of the experimental agents may be insufficient, and that exploration of possible off target effects may be needed to understand the underlying biology of response or resistance.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | N=1920 --> 4000

P2, N=1920, Recruiting, QuantumLeap Healthcare Collaborative | Trial primary completion date: Dec 2020 --> Dec 2025

We leverage machine learning to explore the limitations of using only known mechanisms of action in predicting pCR, and the extent to which biology outside known drug action improves response prediction in the first 10 arms of the trial. Our study involves 986 patients with pre-treatment gene expression and pCR data across 10 treatment arms including inhibitors of HER2: neratinib (N), pertuzumab (P), TDM1/P; AKT (MK-2206; M); IGF1R (ganitumab); HSP90 (ganetespib); PARP/DNA repair (veliparib/carboplatin; VC); ANG1/2 (AMG386); immune checkpoints (pembrolizumab; Pembro); and a shared control arm (Ctr). Our results suggests that hypothesis driven analysis restricted to assumed mechanisms of action of the experimental agents may be insufficient, and that exploration of possible off target effects may be needed to understand the underlying biology of response or resistance.

Treatments included paclitaxel alone (or with trastuzumab (H) in HER2+) or combined with investigational agents: veliparib/carboplatin (VC); neratinib; MK2206; ganitumab; ganetespib; AMG386; TDM1/pertuzumab (P); H/P; and pembrolizumab (Pembro). Molecular phenotypes reflecting proliferation, immune engagement, HER2-activation, luminal/ER-signaling, and DNA repair deficiency may provide a roadmap to guide treatment prioritization for emerging therapeutics.