FDA Grants CB-839 Fast Track Designation for mRCC

CB-839 has been granted Fast Track designation by the FDA in combination with cabozantinib for the treatment of patients with metastatic renal cell carcinoma who have received 1 or 2 prior lines of therapy, according to Calithera Biosciences, the manufacturer of the first-in-class glutaminase inhibitor.

Nizar Tannir, MD

CB-839 has been granted Fast Track designation by the FDA in combination with cabozantinib (Cabometyx) for the treatment of patients with metastatic renal cell carcinoma (mRCC) who have received 1 or 2 prior lines of therapy, according to Calithera Biosciences, the manufacturer of the first-in-class glutaminase inhibitor. Eligible prior lines of therapy include at least 1 vascular endothelial growth factor tyrosine kinase inhibitor or the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The Fast Track designation was based on results from a phase I trial in which CB-839 showed encouraging activity when combined with cabozantinib or everolimus (Afinitor) in heavily pretreated patients with mRCC.

The FDA’s Fast Track program is designed to accelerate the development, review, and approval of drugs that treat serious and life-threatening conditions. The program will now allow Calithera to interact with the FDA more often to aid in the expedited development of the agent.

“We are pleased that CB-839 has been granted Fast Track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our glutaminase inhibitor as an important new therapy for patients with advanced or metastatic renal cell carcinoma who have failed prior systemic therapy,” Susan M. Molineaux, PhD, founder, chief executive officer, and president of Calithera Biosciences, said in a statement.

The dose-escalation portion of the ongoing phase I study (NCT 02071862) enrolled patients with locally advanced, metastatic and/or refractory solid tumors. Patients received CB-839 capsules orally 2 or 3 times daily in 21-day cycles.

Part 2 enrolled patients with triple-negative breast cancer (TNBC), non—small cell lung cancer (NSCLC), RCC, mesothelioma, fumarate hydratase-deficient tumors, SDH–deficient gastrointestinal stromal tumors (GIST), SDH-deficient non-GIST tumors, tumors harboringIDH1orIDH2mutations, and tumors harboring c-MYC amplifications. Patients also received CB-839 monotherapy in part 2.

As an extension of parts 1 and 2, patients were treated with CB-839 in combination with a standard chemotherapy backbone. Patients with locally advanced or metastatic TNBC were treated with added paclitaxel, patients with advanced clear cell RCC or papillary RCC were treated with everolimus in combination with CB-839, patients with advanced NSCLC lacking theEGFRT790M mutation were treated with erlotinib (Tarceva) and CB-839, patients with NSCLC harboring KRASmutations were treated with added docetaxel, and patients with histologically confirmed diagnosis of locally advanced, inoperable, or metastatic RCC treated with cabozantinib plus CB-839.

In a poster presentation at the 2018 Genitourinary Cancers Symposium, Nizar Tannir, MD, of The University of Texas MD Anderson Cancer Center, et al, presented results for 12 eligible patients treated with CB-839 and cabozantinib and 27 patients treated with CB-839 and everolimus.

CB-839 was administered in doses varying from 400 to 800 mg twice daily with a fixed standard oral dose of cabozantinib and everolimus in a 28-day cycle. While a maximum-tolerated dose was not found, 800 mg twice daily was recommended as the phase II dose of CB-839.

In the CB-839 plus cabozantinib cohort, a favorable objective response rate of 40% was demonstrated in patients with clear cell histology (n = 10) and 33% among patients with all histologies, with a disease control rate of 100% across all patients. Across the entire group, 4 patients (33%) achieved a partial response and 8 patients (67%) achieved stable disease.

A total of 27 patients were enrolled in the CB-839/everolimus (n = 17) and expansion (n = 10) cohorts (7 at 400 mg dosage, 13 at 600 mg, 7 at 800 mg).

In the cohort, best responses among 24 evaluable patients included 1 partial response and 21 patients who achieved stable disease for a disease control rate of 92%. The median progression-free survival (PFS) seen in this cohort was 5.8 months.

In the CB-839/cabozantinib group, the most common treatment-related adverse events (AEs) of any grade were diarrhea (52%), alanine transaminase increase (50%), and aspartate transaminase increase (42%). The most common AEs in the CB-839/everolimus group included decreased appetite (33%), rash (30%), and anemia (26%). Grade ≥3 AEs occurred in 33% of patients in the CB-839/cabozantinib cohort and in 48% in the CB-839/everolimus group, with 3 cases of grade ≥3 fatigue.

Among the patients treated with added everolimus, there was 1 dose-limiting toxicity (DLT) at the 400-mg dosage of CB-839 of grade ≥3 thrombocytopenia. In the cabozantinib-treated cohort, 1 DLT of grade ≥3 thrombocytopenia was observed at the 600-mg dosage of CB-839.

While Calithera Biosciences plans to investigate the CB-839/everolimus combination further in the phase II ENTRATA trial, the results for the CB-839/cabozantinib combination demonstrated promising results, leading to this Fast Track designation.

"Based on these promising clinical results, we plan to initiate a global, randomized phase II trial of CB-839 in combination with cabozantinib in the second quarter of 2018, and focus our efforts on developing a potential new therapeutic option that could benefit patients who have failed their first therapies,” Molineaux said.

The CANTATA trial, a phase II, double-blind, placebo-controlled study of cabozantinib plus CB-839, will be used to further investigate the safety and efficacy of this drug. Currently enrolling patients with mRCC who have had 1-2 prior lines of therapy, the primary endpoint of this study is PFS for evaluating the safety and efficacy of the combination.

Molineaux noted that there are not many treatment options for those with advanced disease and prior treatments. The CANTATA trial will evaluate CB-839’s ability to treat this specific population.

Reference:

Tannir N, Fan AC, Lee RJ, et al. Phase 1 Study of glutaminase (GLS) inhibitor CB-839 combined with either everolimus or cabozantinib in patients with clear cell and papillary metastatic renal cell cancer (mRCC). Presented at: 2018 Genitourinary Cancers Symposium; San Francisco, CA, February 8-10, 2018. Abstract 603.