Phase Ib Study of Axatilimab in Combination With Olaparib in BRCA1/2 and PALB2- Associated Metastatic HER2-negative Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- Axatilimab
- Conditions
- Breast Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 20
- Locations
- 3
- Primary Endpoint
- Recommended Phase 2 Dose (RP2D)
- Status
- Recruiting
- Last Updated
- 8 months ago
Overview
Brief Summary
This research is being done to evaluate the safety and tolerability of the new drug, axatilimab, in combination with olaparib (a standard of care treatment) in Breast Cancer 1/2 genes (BRCA 1/2) and PALB2 associated HER2-negative metastatic breast cancer.
The names of the study drugs involved in this study are:
- Axatilimab (a type of antibody)
- Olaparib (a type of PARP inhibitor)
Detailed Description
This is a non-randomized, open-label, proof-of-concept phase 1 study to evaluate the safety and tolerability of a drug known as Axatilimab in combination with the drug Olaparib in BRCA1/2 and PALB2 associated HER2-negative breast cancer. The U.S. Food and Drug Administration (FDA) has not approved axatilimab as a treatment for any disease. The FDA has approved olaparib as a treatment option for BRCA1/2 and PALB2 associated HER2-negative breast cancer, and it is considered standard of care for those types of breast cancer. The FDA has approved olaparib for metastatic (breast cancer that has spread) BRCA1/2 associated HER2-negative breast cancer. The research study procedures include screening for eligibility, study treatment in-clinic visits, tumor biopsies, blood tests, Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, and electrocardiograms. Participation in this research study is expected to last for as long as there is clinical benefit and participants will be followed for a maximum of three years after finishing study treatment. It is expected that about 16-20 people will take part in this research study. Incyte Corporation is funding this research study and providing Axatilimab.
Investigators
Filipa Lynce, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must have histologically or cytologically confirmed metastatic or unresectable HER2 negative breast cancer, including HER2 low (IHC 2+/ISH-, IHC 1+). Any ER and PR expressions are permitted but must be known. Patients with hormone receptor (HR) positive disease, defined by either ER and/or PR positivity, must have progressed or are intolerant to all available endocrine therapy regimens, or not candidates to further endocrine therapy-based approaches.
- •Documented germline or somatic mutation in BRCA1, BRCA2, or germline mutation in PALB2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Testing may be completed by any CLIA-certified laboratory.
- •Participants must have evaluable or measurable disease per RECIST 1.1 criteria. NOTE: If the only site of measurable of disease has been previously irradiated, there must be evidence of post-radiation progression.
- •Patients must have received no more than 2 prior lines of cytotoxic chemotherapy for metastatic disease. Antibody drug conjugates will count towards prior lines of cytotoxic chemotherapy, as well as checkpoint inhibitors. For the purposes of this study, prior treatment with hormonal therapy and non-hormonal targeted therapy, as well as the combination of an aromatase inhibitor and everolimus, are not counted as a prior cytotoxic therapy.
- •Age ≥18 years.
- •ECOG performance ≤
- •Participants must meet the following organ and marrow function as defined below:
- •leukocytes ≥ 3000/mcL
- •absolute neutrophil count ≥ 1.5 x 109/L
- •platelets ≥ 100 x 109/L
Exclusion Criteria
- •Clinical progression on a PARP inhibitor, or within 12 months of receipt of a PARP inhibitor, including but not limited to olaparib.
- •Any previous treatment with CSF1R antibody.
- •Patients who have had prior systemic chemotherapy, immune therapy, or investigational therapy within three weeks of initiation of protocol therapy. Endocrine therapy must have been discontinued at least 7 days prior to initiation of protocol therapy. Patients may receive bisphosphonates or denosumab during the study.
- •Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia, are excluded.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to axatilimab or olaparib.
- •Participants receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP450 enzyme(s) are ineligible. This also includes strong or moderate CYP3A inhibitors and inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference.
- •Participants with a QTcF of \>470msec on screening ECG
- •Patients with a history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML
- •Participants unable to swallow orally administered medication and participants with gastrointestinal disorders that are likely to interfere with absorption of the study medications in the opinion of the treating investigator (e.g. malabsorption syndrome or major stomach or bowel resections).
- •Uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Arms & Interventions
Axatilimab + Olaparib
A Bayesian Optimal Interval design will be used to establish the maximum tolerated dose of Axatilimab. Dose reduction and escalation will be per protocol. Participants will complete: * Baseline visit, tumor biopsy, and imaging * Imaging every 8 weeks * Window Phase: --Predetermined dose of Olaparib 2x daily, taken 12 hours apart for 14 days * Combination Treatment Phase: * Cycle 1 through Cycle 2: * Day 1 of 28 day cycle: Tumor biopsy * Days 1 and 15 of 28 day Cycle: Predetermined dose of Axalitimab 1x daily * Days 1 through 28 of 28 day cycle Predetermined dose of Olaparib 2x daily, 12 hours apart * Tumor biopsy after two weeks of Olaparib and at the end of Cycle 2 * Cycle 3 through End of Treatment: * Days 1 and 15 of 28 Day Cycle: Predetermined dose of Axalitimab 1x daily * Predetermined dose of Olaparib 2x daily, taken 12 hours apart * End of Treatment Visit with imaging * Follow Up: Every 6 months for 3 years. Imaging will be every 10 weeks.
Intervention: Axatilimab
Axatilimab + Olaparib
A Bayesian Optimal Interval design will be used to establish the maximum tolerated dose of Axatilimab. Dose reduction and escalation will be per protocol. Participants will complete: * Baseline visit, tumor biopsy, and imaging * Imaging every 8 weeks * Window Phase: --Predetermined dose of Olaparib 2x daily, taken 12 hours apart for 14 days * Combination Treatment Phase: * Cycle 1 through Cycle 2: * Day 1 of 28 day cycle: Tumor biopsy * Days 1 and 15 of 28 day Cycle: Predetermined dose of Axalitimab 1x daily * Days 1 through 28 of 28 day cycle Predetermined dose of Olaparib 2x daily, 12 hours apart * Tumor biopsy after two weeks of Olaparib and at the end of Cycle 2 * Cycle 3 through End of Treatment: * Days 1 and 15 of 28 Day Cycle: Predetermined dose of Axalitimab 1x daily * Predetermined dose of Olaparib 2x daily, taken 12 hours apart * End of Treatment Visit with imaging * Follow Up: Every 6 months for 3 years. Imaging will be every 10 weeks.
Intervention: Olaparib
Outcomes
Primary Outcomes
Recommended Phase 2 Dose (RP2D)
Time Frame: Up to 4 weeks
If the MTD is identified as 3mg/kg, we will complete enrollment of 10 pts at the 1 mg/kg dose level, to determine if there is biological effectiveness (and clinical efficacy) at the lower dose level.
Maximum Tolerated Dose (MTD)
Time Frame: Up to 4 weeks
MTD is determined by Bayesian optimal interval (BOIN) design, where the target toxicity rate for the MTD is 0.25 and the maximum sample size is 20.
Secondary Outcomes
- Median Progression Free Survival (PFS)(Up to 6 months)
- Objective Response Rate (ORR)(Up to 6 months)