Olaparib and Onalespib in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple-Negative Breast Cancer

NCT02898207 | Completed Phase 1 Results DMC FDA Drug

• 4 other identifiers: NCI-2016-0136417-71510031UM1CA186709
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 8

Brief Summary

This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back (recurrent). Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

Metastatic High Grade Fallopian Tube Serous Adenocarcinoma; Metastatic Malignant Solid Neoplasm; Metastatic Primary Peritoneal Serous Adenocarcinoma; Metastatic Triple-Negative Breast Carcinoma; Platinum-Resistant Fallopian Tube Carcinoma; Platinum-Resistant Ovarian Carcinoma; Platinum-Resistant Primary Peritoneal Carcinoma; Recurrent Breast Carcinoma; Recurrent High Grade Fallopian Tube Serous Adenocarcinoma; Recurrent High Grade Ovarian Serous Adenocarcinoma; Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma; Recurrent Triple-Negative Breast Carcinoma; Refractory Fallopian Tube Serous Adenocarcinoma; Refractory Ovarian Serous Adenocarcinoma; Refractory Primary Peritoneal Serous Adenocarcinoma; Refractory Triple-Negative Breast Carcinoma; Unresectable High Grade Fallopian Tube Serous Adenocarcinoma; Unresectable Malignant Solid Neoplasm; Unresectable Primary Peritoneal Serous Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of Olaparib Administered in Combination With Onalespib

  MTD was determined by testing increasing doses of the combination of olaparib PO and onalespib IV within dose escalation cohorts consisting of 3 to 6 evaluable participants. MTD reflects the highest dose combination that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Enrollment to this study was suspended prior to completion of the dose escalation due to discontinuation of further development of onalespib. A true single MTD therefore could not be determined. The two dose levels included in this outcome measure represent the highest well-tolerated dose combinations (Dose Level 2 \[DL2\]: Olaparib 300 mg PO BID and Onalespib 40 mg/m\^2 IV; and Dose Level 2a \[DL2a\]: Olaparib 200 mg PO BID and Onalespib 80 mg/m\^2 IV).

  Up to 35 days for each dose level cohort

• Maximum Tolerated Dose (MTD) of Onalespib Administered in Combination With Olaparib

  MTD was determined by testing increasing doses of the combination of olaparib PO and onalespib IV within dose escalation cohorts consisting of 3 to 6 evaluable participants. MTD reflects the highest dose combination that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

  Up to 35 days for each dose level cohort

Secondary Outcomes (4)

• Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)

  Within Cycles 0 and 1 (up to 35 days).

• Number of Participants Who Experienced Treatment-Related Toxicities

  Up to 67 weeks

• Number of Participants With Objective Responses by RECIST 1.1

  Up to 63 weeks

• Number of Participants Progression-Free for At Least 24 Weeks by RECIST 1.1

  Up to 24 weeks

Study Arms (6)

Dose Level 0: Olaparib 200 mg and Onalespib 20 mg/m^2

EXPERIMENTAL

Dose Level 0 (DL0): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 20 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Dose Level 1: Olaparib 200 mg and Onalespib 40 mg/m^2

EXPERIMENTAL

Dose Level 1 (DL1): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Dose Level 2: Olaparib 300 mg and Onalespib 40 mg/m^2

EXPERIMENTAL

Dose Level 2 (DL2): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Dose Level 3: Olaparib 300 mg and Onalespib 80 mg/m^2

EXPERIMENTAL

Dose Level 3 (DL3): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Dose Level 2a: Olaparib 200 mg and Onalespib 80 mg/m^2

EXPERIMENTAL

Dose Level 2a (DL2a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Dose Level 3a: Olaparib 200 mg and Onalespib 120 mg/m^2

EXPERIMENTAL

Dose Level 3a (DL3a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 120 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Olaparib; Drug: Onalespib

Interventions

Olaparib DRUG

Given PO

Also known as: AZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281

Dose Level 0: Olaparib 200 mg and Onalespib 20 mg/m^2; Dose Level 1: Olaparib 200 mg and Onalespib 40 mg/m^2; Dose Level 2: Olaparib 300 mg and Onalespib 40 mg/m^2; Dose Level 2a: Olaparib 200 mg and Onalespib 80 mg/m^2; Dose Level 3: Olaparib 300 mg and Onalespib 80 mg/m^2; Dose Level 3a: Olaparib 200 mg and Onalespib 120 mg/m^2

Onalespib DRUG

Given IV

Also known as: AT 13387, AT-13387, AT13387

Dose Level 0: Olaparib 200 mg and Onalespib 20 mg/m^2; Dose Level 1: Olaparib 200 mg and Onalespib 40 mg/m^2; Dose Level 2: Olaparib 300 mg and Onalespib 40 mg/m^2; Dose Level 2a: Olaparib 200 mg and Onalespib 80 mg/m^2; Dose Level 3: Olaparib 300 mg and Onalespib 80 mg/m^2; Dose Level 3a: Olaparib 200 mg and Onalespib 120 mg/m^2

Eligibility Criteria

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

You may qualify if:

• For the dose escalation cohort, patients must have histologically or cytologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
• For the dose escalation cohort, patients may have received any number of prior therapies
• For the dose expansion cohort, participants must have histologically or cytologically confirmed diagnosis of either:
• Ovarian, fallopian tube, or primary peritoneal cancer of high grade serous histology which has recurred despite standard therapy; up to 3 prior lines in the platinum resistant setting (i.e. up to 3 lines after patients have become platinum resistant); patients may have received unlimited lines while platinum sensitive
• Triple-negative breast cancer (TNBC) which has recurred despite standard therapy; recurrent TNBC needs to have metastatic disease and patients with an in breast recurrence are not eligible; up to 4 prior lines in the recurrent setting for patients with triple-negative breast cancer are allowed
• For the dose expansion cohort, patients with ovarian, fallopian tube or primary peritoneal cancer must have platinum resistant disease defined as progression within 6 months after last platinum regimen; platinum refractory disease is allowed
• For the dose expansion cohort, patients with triple-negative breast cancer may not be BRCA1/2 germline mutation carriers
• Because no dosing or adverse event data are currently available on the use of olaparib in combination with AT13387 in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• There must be availability of a formalin-fixed, paraffin-embedded tumor specimen
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky \> 60%)
• Life expectancy of greater than 12 weeks
• Leukocytes \>= 3,000/mcL
• Hemoglobin \>= 10 g/dL with no blood transfusion in the past 28 days
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• All acute, clinically significant treatment-related toxicity from prior therapy, except for alopecia, must have resolved to grade =\< 1
• Patients who are receiving any other investigational agents
• Patients with known active or history of brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and AT13387 used in study
• Uncontrolled intercurrent illness including, but not limited to, 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
• Pregnant women are excluded from this study because olaparib and AT13387 are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AT13387 or olaparib, breastfeeding should be discontinued if the mother is treated with olaparib or AT13387
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with olaparib or AT13387; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Known history of QT/corrected QT (QTc) prolongation or torsades de pointes (TdP); patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drugs
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible; the study team should check a frequently-updated medical reference for a list of drugs to avoid or minimize use of; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Participants with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (8)

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis; Triple Negative Breast Neoplasms; Breast Neoplasms

Interventions

olaparib; (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Dr. Panagiotis Konstantinopoulos
• Organization: Dana-Farber Cancer Institute

Panagiotis_Konstantinopoulos@dfci.harvard.edu

617-632-5269

Study Officials

• Panagiotis A Konstantinopoulos

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 12, 2016
• First Posted: September 13, 2016
• Study Start: May 19, 2017
• Primary Completion: July 29, 2020
• Study Completion: January 14, 2022
• Last Updated: April 26, 2023
• Results First Posted: April 26, 2023

Record last verified: 2023-04

Locations

US (8)