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Combination of Olaparib and Navitoclax in Women With HGSC and TNBC

Primary Purpose

High Grade Serous Carcinoma, Triple Negative Breast Cancer, Ovarian Cancer

Status

Recruiting

Phase

Phase 1

Locations

Canada

Study Type

Interventional

Intervention

Olaparib tablet

Navitoclax

About this trial

This is an interventional treatment trial for High Grade Serous Carcinoma focused on measuring BRCA1 Mutation, BRCA2 Mutation, PALB2 Gene Mutation, Olaparib, Navitoclax, Bcl-2, Bcl-xL, Bax, Mcl-1, Bcl-W, Bak, Bok, Bid, Bim, Bad, Bik, Noxa, Puma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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 additionnal 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 drugsincluding 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.

Sites / Locations

Sunnybrook Research Institute/Odette Cancer CentreRecruiting
Princess Margaret Cancer CentreRecruiting
CHUMRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single

Arm Description

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

Outcomes

Primary Outcome Measures

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

The RP2D will be determined based on an evaluation of multiple endpoints, which will include the DLT( dose limiting toxicity) rate.

Secondary Outcome Measures

Cmax: the maximum drug concentration.

The maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.

Tmax: time to reach the maximum drug concentration.

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.

Full Information

NCT ID

NCT05358639

First Posted

March 22, 2022

Last Updated

July 6, 2023

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT05358639

Brief Title

Combination of Olaparib and Navitoclax in Women With HGSC and TNBC

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 9, 2022 (Actual)

Primary Completion Date

April 28, 2024 (Anticipated)

Study Completion Date

April 28, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sunnybrook Health Sciences Centre

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

High Grade Serous Carcinoma, Triple Negative Breast Cancer, Ovarian Cancer

Keywords

BRCA1 Mutation, BRCA2 Mutation, PALB2 Gene Mutation, Olaparib, Navitoclax, Bcl-2, Bcl-xL, Bax, Mcl-1, Bcl-W, Bak, Bok, Bid, Bim, Bad, Bik, Noxa, Puma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

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.

Masking

None (Open Label)

Allocation

N/A

Enrollment

36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Single

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Olaparib tablet

Other Intervention Name(s)

Lynparza

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Navitoclax

Other Intervention Name(s)

ABT-263

Intervention Description

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).

Primary Outcome Measure Information:

Title

Description

The RP2D will be determined based on an evaluation of multiple endpoints, which will include the DLT( dose limiting toxicity) rate.

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Cmax: the maximum drug concentration.

Description

The maximum drug concentration will be measured in blood samples as part of the PK profile of olaparib and navitoclax when given in combination.

Time Frame

2 years

Title

Tmax: time to reach the maximum drug concentration.

Description

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.

Time Frame

2 years

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Helen Mackay

Phone

416-480-5145

helen.mackay@sunnybrook.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Helen MacKay, MD

Organizational Affiliation

Sunnybrook Cancer Centre

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sunnybrook Research Institute/Odette Cancer Centre

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M4N 3M5

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Helen MacKay, MD

First Name & Middle Initial & Last Name & Degree

Rossanna Pezo, MD

First Name & Middle Initial & Last Name & Degree

Katarzyna Jerzak, MD

First Name & Middle Initial & Last Name & Degree

Lilian Gien, MD

Facility Name

Princess Margaret Cancer Centre

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1Z5

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Stephanie Lheureux, MD

First Name & Middle Initial & Last Name & Degree

Neesha Dhani, MD

First Name & Middle Initial & Last Name & Degree

Gita Bhat, MD

First Name & Middle Initial & Last Name & Degree

Robert C. Grant, MD

First Name & Middle Initial & Last Name & Degree

Husam Ali Mahmoud Alqaisi, MD

First Name & Middle Initial & Last Name & Degree

Amit M. Oza, MD

Facility Name

CHUM

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H2X 0A9

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Diane Provencher, MD

First Name & Middle Initial & Last Name & Degree

Annick Pina, MD

First Name & Middle Initial & Last Name & Degree

Beatrice Cormier, MD

First Name & Middle Initial & Last Name & Degree

Omar Moreira-Basha, MD

First Name & Middle Initial & Last Name & Degree

Thomas Warkus, MD

First Name & Middle Initial & Last Name & Degree

Vanessa Samouëlian, MD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Combination of Olaparib and Navitoclax in Women With HGSC and TNBC

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