Combination of Olaparib and Navitoclax in Women with HGSC and TNBC

NCT05358639 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: Exactis-03
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 3

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  2 years

Secondary Outcomes (2)

• Cmax: the maximum drug concentration.

  2 years

• Tmax: time to reach the maximum drug concentration.

  2 years

Study Arms (1)

Single

EXPERIMENTAL

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; Drug: Navitoclax

Interventions

Olaparib tablet DRUG

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.

Also known as: Lynparza

Single

Navitoclax DRUG

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).

Also known as: ABT-263

Single

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead
• Exactis Innovation: collaborator
• Centre hospitalier de l'Université de Montréal (CHUM): collaborator
• Princess Margaret Hospital, Canada: collaborator

Study Sites (3)

Sunnybrook Research Institute/Odette Cancer Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 1Z5, Canada

Location

CHUM

Montreal, Quebec, H2X 0A9, Canada

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Ovarian Neoplasms

Interventions

olaparib; navitoclax

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Helen MacKay, MD

  Sunnybrook Cancer Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 22, 2022
• First Posted: May 3, 2022
• Study Start: November 9, 2022
• Primary Completion: March 30, 2025
• Study Completion: April 28, 2025
• Last Updated: November 18, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3)