Combination of Olaparib and Navitoclax in Women With HGSC and TNBC

July 6, 2023 updated by: Sunnybrook Health Sciences Centre

A Phase I Trial of the Combination of Olaparib and Navitoclax in Women With High Grade Serous Epithelial Ovarian Cancer and Triple Negative Breast Cancer

The purpose of this Phase I study is to determine if the PARP inhibitor olaparib can be safely combined with navitoclax, an inhibitor of Bcl-2/Bcl-XL, in women with TNBC who have somatic or germline mutations in breast cancer gene one (BRCA1) and breast cancer gene two (BRCA2) BRCA1/2 or PALB2 and in women with recurrent HGSC who have progressed greater than 6 months since their last platinum containing chemotherapy. The trial is designed as an open- label multi-center Phase I interventional and translational study. It will identify the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D of olaparib combined with navitoclax for study in Phase II. There is a plan for a follow on Phase II study depending on the results obtained during this Phase I trial.The rationale for this study is that for a subset of patients, olaparib, will increase tumor cell survival dependence on inhibition of cell death by Bcl 2/Bcl- XL. Thus, navitoclax will augment apoptosis induced by PARP inhibition with olaparib.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

In this trial, olaparib will be delivered alone for 14 days with the hypothesis that priming of the apoptotic machinery will be required prior to introduction of the senolytic agent (navitoclax). To date navitoclax and olaparib have not been combined in the clinic. The Phase I study will therefore be conducted to define the recommended Phase II dose (RP2D). A plan for a future Phase II study will depend on the results obtained during this Phase I trial. Based on the potential for overlapping toxicity (particularly hematologic toxicity) an interrupted dosing schedule will be used for the navitoclax. Based on preclinical studies it is believed that intermittent delivery of the senolytic agent is in line with the proposed mechanism of action. Subsequently the dose of navitoclax will be escalated with a fixed dose of olaparib in 28-day cycles.

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4N 3M5
        • Recruiting
        • Sunnybrook Research Institute/Odette Cancer Centre
        • Principal Investigator:
          • Helen MacKay, MD
        • Sub-Investigator:
          • Rossanna Pezo, MD
        • Sub-Investigator:
          • Katarzyna Jerzak, MD
        • Sub-Investigator:
          • Lilian Gien, MD
      • Toronto, Ontario, Canada, M5G 1Z5
        • Recruiting
        • Princess Margaret Cancer Centre
        • Principal Investigator:
          • Stephanie Lheureux, MD
        • Sub-Investigator:
          • Neesha Dhani, MD
        • Sub-Investigator:
          • Gita Bhat, MD
        • Sub-Investigator:
          • Robert C. Grant, MD
        • Sub-Investigator:
          • Husam Ali Mahmoud Alqaisi, MD
        • Sub-Investigator:
          • Amit M. Oza, MD
    • Quebec
      • Montreal, Quebec, Canada, H2X 0A9
        • Recruiting
        • CHUM
        • Principal Investigator:
          • Diane Provencher, MD
        • Sub-Investigator:
          • Annick Pina, MD
        • Sub-Investigator:
          • Beatrice Cormier, MD
        • Sub-Investigator:
          • Omar Moreira-Basha, MD
        • Sub-Investigator:
          • Thomas Warkus, MD
        • Sub-Investigator:
          • Vanessa Samouëlian, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion

  • Histologically confirmed:

    • Recurrent metastatic HGSC of ovarian, peritoneal or fallopian tube origin with radiological progression greater than 6 months from last platinum based therapy.

    • Metastatic TNBC: tumors that are known to have deleterious somatic or germline mutations in BRCA1, BRCA2, or PALB2.

      • Age ≥ 18 years of age.
      • ECOG Performance Status of 0, 1 or 2 within 7 days prior to registration (Appendix 4).
      • No more than two (2) prior lines of treatment for TNBC.
      • No limit on the number of prior lines for HGSC.
      • Prior maintenance or treatment with PARP inhibitor is allowed provided progression did not occur on or within 6 months of discontinuing the drug. Patients must be considered able to tolerate olaparib as per dosing regimen in this study.
      • Patients must be able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption.
      • Patients must be able and willing to undergo study related procedures (biopsies pre and on treatment) and to provide archival tissue, if available.
      • Patients must have a life expectancy ≥16 weeks.
      • Patients must have adequate organ and marrow function measured within 28 days prior to administration of study drug

  • Patients must have measurable disease as defined by RECIST 1.1. Progressive irradiated lesions considered but would require an additional out of field measurable lesion.

    • Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.

Exclusion

  • Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within 30 days prior to first dose of investigational products (IPs).
  • Due to the expected dose-limiting toxicity of thrombocytopenia, the following concomitant medications are not allowed within 14 days of the olaparib lead-in period: Warfarin, clopidogrel (plavix), ibuprofen, tirofiban (aggrastat), and other anticoagulants drugs including low molecular weight heparin, or herbal supplements that affect platelet function are excluded. Caution should be exercised when dosing Navitoclax concurrently with CYP2C8 and CYP2C9 substrates.
  • Due to the known effects of navitoclax on platelet counts, patients with active bleeding or thrombocytopenia-associated bleeding within 1 year, active peptic ulcer disease or potentially hemorrhagic esophagitis or gastritis, a requirement for concurrent therapeutic anticoagulants, or a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, or refractoriness to platelet transfusions.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single
Olaparib tablet will be administered alone for 14 days at a starting dose of 200 mg twice daily (bid). Subsequently olaparib will be administered continuously over 28 days at a fixed dose and the dose of navitoclax will be escalated. Navitoclax will be administered daily. The initial dose of olaparib 200 mg has been selected after considering the single agent Phase I/II dose based and on ongoing combination studies on expected toxicity and evidence for reduced PARP inhibition
Drug: Olaparib tablet
Olaparib tablet will be administered alone for 14 days at a starting dose of 200 mg twice daily. Subsequently olaparib will be administered continuously over 28 days at a fixed dose and the dose of navitoclax will be escalated.
Other Names:
  • Lynparza
Drug: Navitoclax
For navitoclax, a lead-in of 7 days at 150 mg PO will be used prior to dose escalation. The DLT period for dose levels above DL 3 will include the 14-day olaparib alone lead-in, the 7 days combination with navitoclax at 150 mg and the first 28 day cycle of the combination of olaparib and navitoclax cycle at the full dose level dosing (49 days).
Other Names:
  • ABT-263

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To define a dose and schedule of navitoclax (Recommended Phase II Dose, RP2D) that can be combined safely with Olaparib in women with metastatic recurrent high grade serous ovarian cancer (HGSC) and triple negative breast cancer (TNBC) for further study
Time Frame: 2 years
The RP2D will be determined based on an evaluation of multiple endpoints, which will include the DLT( dose limiting toxicity) rate.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cmax: the maximum drug concentration.
Time Frame: 2 years
The maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.
2 years
Tmax: time to reach the maximum drug concentration.
Time Frame: 2 years
The time to reach maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

Centre hospitalier de l'Université de Montréal (CHUM)
Exactis Innovation
Princess Margaret Hospital, Canada

Investigators

  • Principal Investigator: Helen MacKay, MD, Sunnybrook Cancer Centre

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 9, 2022

Primary Completion (Estimated)

April 28, 2024

Study Completion (Estimated)

April 28, 2025

Study Registration Dates

First Submitted

March 22, 2022

First Submitted That Met QC Criteria

April 27, 2022

First Posted (Actual)

May 3, 2022

Study Record Updates

Last Update Posted (Actual)

July 7, 2023

Last Update Submitted That Met QC Criteria

July 6, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Exactis-03

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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