A Phase II, Open-Label, Study of Olaparib in Combination With Either Durvalumab (MEDI4736), Selumetinib or Capivasertib, or Ceralasertib Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Biopsy
- Conditions
- Anatomic Stage IV Breast Cancer AJCC v8
- Sponsor
- Gordon Mills, MD, PhD
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Objective Response Rate (ORR)
- Status
- Terminated
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase II study assesses the efficacy of the combination of olaparib with durvalumab, selumetinib, or capivasertib or ceralasertib alone in the treatment of patients with metastatic triple negative breast cancer (TNBC). Olaparib may stop growth of tumor cells by inhibiting some of the enzymes (ADP ribose polymerase [PARP]) needed for cell growth. Durvalumab, a monoclonal antibody, inhibits the growth and spread of tumors by stimulating the patient's antitumor immune response. Selumetinib, capivasertib, and ceralasertib are inhibitor drugs that may stop the growth of tumor cells by blocking some of the enzymes (MEK, AKT, ATR) needed for cell growth. Giving olaparib together with durvalumab, selumetinib, or capivasertib or giving ceralasertib alone may provide an effective method to treat patients with metastatic triple negative breast cancer.
Detailed Description
PRIMARY OBJECTIVE: I. Assess overall response to treatment. SECONDARY OBJECTIVES: I. Assess participant benefit from treatment. II. Determine the time to disease progression following response to study therapy. III. Determine time to first disease progression or death of participants enrolled on the study. IV. Determine survival of participants enrolled on the study. V. Assess safety and tolerability of the proposed therapy. EXPLORATORY OBJECTIVES: I. To assess a change in quality of life (QOL) as measured by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) in each treatment arm. II. To assess a change in QOL as measured by Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23) in each treatment arm. III. Examine response rates depending on tumor characteristics. IV. Identify predictive biomarkers of sensitivity to therapy. V. Identify emerging mechanism of resistance to therapy. VI. Determine changes in tumor cells and the tumor microenvironment induced by PARP inhibitors. OUTLINE: This is an open-label, multi-arm phase II study of olaparib in combination with durvalumab, selumetinib, or capivasertib, or ceralasertib monotherapy. LEAD IN: Patients with biopsy proven TNBC undergo a pre-treatment biopsy. At the 2 week mark, patients then undergo a repeat on-treatment biopsy. Patients also receive olaparib orally (PO) twice daily (BID) on days 1-28 for one cycle. Treatment repeats every 28 days for up to 1 cycle in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 4 arms based on predefined molecular tumor characteristics. ARM I: Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles. ARM II: Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles. ARM III: Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles. ARM IV: Patients receive ceralasertib PO BID on days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles. At the completion of all on-study procedures, patients are followed up every 6 months for disease and survival outcomes up to 1 year. Patients will be asked to submit an optional tumor biopsy in the event of disease progression.
Investigators
Gordon Mills, MD, PhD
IND Holder
OHSU Knight Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Ability to understand and the willingness to sign a written informed consent document
- •Participants are \>= 18 years old at time of informed consent.
- •Metastatic TNBC, as defined by:
- •Estrogen receptor (ER) and progesterone receptor (PR) negative as defined as ER \< 10% and PR \< 10% by immunohistochemistry according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing
- •HER2 non-amplified per ASCO/CAP guidelines, defined as:
- •IHC score 0/1+
- •IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to CEP17 \< 2.0, and if reported, average HER2 gene copy number \< 4 signals/cells; or
- •ISH non-amplified with a ratio of HER2 to CEP17 \<2.0, and if reported, average HER2 gene copy number \< 4 signals/cells
- •Participants with or without germline BRCA mutated TNBC are eligible for study participation
- •Participants must have at least one measurable site of disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 that is amenable to biopsy
Exclusion Criteria
- •Any concurrent anticancer treatment
- •Individuals in the follow-up phase of a prior investigational study may participate as long as it has been 4 weeks since last dose of the previous investigational agent or device
- •Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) is allowed
- •Participant's with tumors showing androgen receptor (AR) \>= 80% by immunohistochemistry are excluded
- •Other malignancy unless curatively treated with no evidence of disease for \>= 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma. Participants with a personal history of treated early stage breast cancer whose natural history or treatment does not have the potential to interfere with the safety or efficacy endpoints of the trial, per investigator assessment, are eligible
- •Participants with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
- •Participant received prior anticancer therapy such as targeted therapies, or systemic chemotherapy or radiation (except for palliative reasons) within the past 3 weeks, or 5 half-lives, whichever is shorter, prior to first day of treatment
- •Participants with known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Patients with brain metastases may participate provided they do not have symptomatic uncontrolled disease. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. (note: a scan to confirm the absence of brain metastases is not required)
- •Patients with spinal cord compression are not eligible unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
Arms & Interventions
Arm I (olaparib, durvalumab)
Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Biopsy
Arm I (olaparib, durvalumab)
Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Durvalumab
Arm I (olaparib, durvalumab)
Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Olaparib
Arm I (olaparib, durvalumab)
Patients receive olaparib PO BID on days 1-28 of each cycle and durvalumab intravenously (IV) over 1 hour on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Quality-of-Life Assessment
Arm II (olaparib, selumetinib)
Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Biopsy
Arm II (olaparib, selumetinib)
Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Olaparib
Arm II (olaparib, selumetinib)
Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Quality-of-Life Assessment
Arm II (olaparib, selumetinib)
Patients receive olaparib PO BID on days 1-28 of each cycle and selumetinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Selumetinib
Arm III (olaparib, capivasertib)
Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Biopsy
Arm III (olaparib, capivasertib)
Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Capivasertib
Arm III (olaparib, capivasertib)
Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Olaparib
Arm III (olaparib, capivasertib)
Patients receive olaparib PO BID on days 1-28 of each cycle and capivasertib PO BID 4 days on and 3 days off of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Quality-of-Life Assessment
Arm IV (ceralasertib)
Patients receive ceralasertib PO BID on days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Biopsy
Arm IV (ceralasertib)
Patients receive ceralasertib PO BID on days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Ceralasertib
Arm IV (ceralasertib)
Patients receive ceralasertib PO BID on days 1-14 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients deriving clinical benefit from treatment may, at the investigator's discretion and in the absence of disease progression or unacceptable toxicity, continue on therapy beyond the planned 13 cycles.
Intervention: Quality-of-Life Assessment
Outcomes
Primary Outcomes
Objective Response Rate (ORR)
Time Frame: End of treatment (Up to 24 months)
Using the efficacy analysis set, the estimate of ORR will be measured independently for each treatment arm and reported with 95% exact confidence interval. Participants who, within their respective treatment arm, achieve a complete response (CR) or a partial response (PR) that is confirmed on a second scan at least 4 weeks later on the current protocol will be qualified as achieving a response, and will count towards the ORR measurement.
Secondary Outcomes
- Clinical Benefit Rate (CBR)(End of treatment (Up to 24 months))
- Progression-free Survival (PFS)(Progression or death (any cause) up to 1 year post treatment)
- Overall Survival (OS)(Death (any cause) up to 1 year post treatment)
- Duration of Response (DOR)(Duration of response was calculated from date of PR/CR (whichever occurred earlier) to EOT.)
- Incidence of Grade 3+ Acute Toxicity: # of Occurrences(Up to 3 months post treatment)
- Incidence of Grade 3+ Acute Toxicity: # of Participants(Up to 3 months post treatment)