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news.Cascadian Therapeutics announced that after a recent meeting with the US Food and Drug Administration (FDA) and discussions with the Company's external Steering Committee, it has amended the HER2CLIMB Phase 2 clinical trial of tucatinib (also known as ONT-380) by increasing the sample size so that, if successful, the trial could serve as a single pivotal study to support registration.
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This decision is supported by the most recent data from the Company's ongoing Phase 1b study evaluating the same "triplet combination" therapy being investigated in the amended Phase 2 trial, which is tucatinib in combination with capecitabine and trastuzumab for patients with metastatic or locally advanced HER2-positive breast cancer, including patients with and without brain metastases.
Tucatinib is an oral, small molecule kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR.
HER2CLIMB is an ongoing randomized, controlled pivotal trial evaluating tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in heavily pre-treated patients with advanced HER2-positive breast cancer with or without brain metastases.
Cascadian Therapeutics President and CEO Scott Myers said: "We are extremely pleased with the outcome of our recent interactions with the FDA, and we have decided to amend the current Phase 2 clinical trial of tucatinib so that, if successful, HER2CLIMB could serve as a single pivotal registration trial and potentially provide us with a more efficient path to market.
"We look forward to continuing a collaborative relationship with the agency and our clinical investigators as we advance the development of tucatinib in combination in the third-line metastatic breast cancer setting where there is no single standard-of-care and a need for more tolerable therapeutic options.
“The improvement in the updated data from our Phase 1b "triplet combination" study reinforces our strategy with tucatinib in this patient population."
Updated Phase 1b trial results for the triplet combination show that the combination (tucatinib with capecitabine and trastuzumab) continues to be well tolerated, with the updated median progression-free survival (PFS) increasing to 7.8 months, an overall response rate (ORR) of 61 percent and a median duration of response (MDR) of 10 months.
Patients in the Phase 1b triplet combination previously received a median of 3 HER2-targeted agents, such as trastuzumab, pertuzumab, lapatinib or T-DM1. Poster presentations on the amended HER2CLIMB pivotal trial and the updated Phase 1b "triplet combination" trial data will be presented at the 2016 San Antonio Breast Cancer Symposium (SABCS), December 6-10, 2016.
Sarah Cannon Research Institute Breast and Gynecology Cancer Research director Erika Hamilton, M.D. said: "The more mature dataset from the Phase 1b trial continues to show tucatinib may be combined with other current targeted therapies to achieve durable responses in patients who have received multiple prior lines of therapy.
"Tucatinib in combination appears to be well-tolerated, potentially making it a highly desirable HER2 therapy for a patient population that vitally needs new options. An active agent showing systemic activity, with a tolerable safety profile and early signs of activity in HER2-positive brain metastases, would represent a meaningful advancement in treating metastatic breast cancer."
HER2CLIMB Pivotal Trial
HER2CLIMB is a randomized (2:1), double-blind, controlled pivotal clinical trial comparing tucatinib vs. placebo in combination with capecitabine and trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and T-DM1.
Following a meeting with the FDA, the primary endpoint remains PFS based upon independent radiologic review, and the sample size will increase to approximately 480 patients, including patients already enrolled in the trial.
Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival.
HER2CLIMB is currently enrolling in the United States and Canada and is expected to expand into Europe, Australia and Israel. Details of the amended HER2CLIMB clinical trial design will be presented in a poster session (OT1-02-09) at SABCS on Wednesday, December 7, 2016 beginning at 5:00 p.m. CST.
Updated Phase 1b Triplet Study Findings at SABCS
Results reported in June 2016 showed a median PFS of 6.3 months and ORR of 58 percent. Updated data from the SABCS poster (P4-21-01) of the Phase 1b study show encouraging safety and anti-tumor activity in patients with and without brain metastases, with an updated median PFS of 7.8 months (a 24 percent improvement over prior median PFS), ORR of 61 percent and a median duration of response of 10 months. Patients with and without brain metastases had similar response rate.
The combination of tucatinib with trastuzumab and capecitabine was well-tolerated. Most treatment-emergent adverse events were Grade 1, with few tucatinib dose reductions and no required prophylactic use of antidiarrheal agents.