Phase 1b Study of Combo Therapy for Metastatic Colorectal Cancer Begins Dosing

Phase 1b Study of Combo Therapy for Metastatic Colorectal Cancer Begins Dosing

OncoMed Pharmaceuticals announced the dosing of the first patient in a Phase 1b clinical study evaluating the combination of its anti-DLL4 /VEGF bispecific antibody (OMP-305B83) and chemotherapy in people with second-line metastatic colorectal cancer (mCC).

The multicenter, open-label, dose escalation and expansion study (NCT02482441) will evaluate the preliminary effectiveness, safety, immunogenicity, pharmacokinetics, and biomarker effects of a combination of anti-DLL4/VEGF bispecific antibody and FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy in mCC patients who have failed first-line treatment, typically bevicizumab and FOLFOX (folinic acid, fluorouracil, oxaliplatin) chemotherapy. The study is currently recruiting patients in six U.S. sites.

”Metastatic colorectal cancer is an indication that we believe may benefit from the combined inhibition of DLL4 and VEGF plus chemotherapy,” Robert Stagg, OncoMed’s vice president, Clinical Research, said in a press release.

“Anti-VEGF therapy plus 5-fluorouracil-based chemotherapy is currently approved in the treatment of second-line metastatic colorectal cancer, and this Phase 1b clinical trial is an opportunity to study the safety and preliminary efficacy of our anti-DLL4/VEGF bispecific antibody in combination with 5-fluorouracil-based chemotherapy and to observe if the multi-pronged mechanism of action may provide signs of enhanced activity.”

The company recently reported interim results of an ongoing open-label Phase 1a dose escalation and expansion clinical trial (NCT02298387) of OMP-305B83 alone in 51 subjects with previously treated solid tumors. Additional patients are being enrolled.

The data, presented during the 28th EORTC-NCI-AACR Molecular Targets and Cancer Symposium, showed that the single-agent treatment resulted in anti-tumor activity, with two of the 46 patients demonstrating a partial response and 12 patients showing reduced tumor volume. One of the two patients with colorectal cancer in this trial also had a reduction in tumor volume.

Treatment with OMP-305B83 alone was generally well-tolerated, with the most commonly treatment-related toxicities including headache, hypertension, and pulmonary hypertension.  These results also were published in the European Journal of Cancer.

Tumor angiogenesis is an important target for cancer therapy, and most currently available  therapies block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways.

The endothelial Notch ligand Dll4 (delta-like 4) is a critical regulator of tumor angiogenesis and a promising anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies.

OncoMed’s anti-DLL4/VEGF bispecific targets both DLL4 on the Notch cancer stem cell pathway and the VEGF receptor, and was developed to have both anti-cancer stem cell, immunomodulatory, and anti-angiogenic activity.

The antibody is the first program based on OncoMed’s BiMAb bispecific platform technology, which enables bispecific antibodies with traditional antibody shape, to enter clinical testing.

OncoMed is planning to soon begin enrolling patients with platinum resistant ovarian cancer in a Phase 1b study evaluating this same drug combination.

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