Talazoparib and HSP90 Inhibitor AT13387 in Treating Patients With Metastatic Advanced Solid Tumor or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple Negative Breast Cancer

A Phase 1 Study of PARP Inhibitor BMN 673 and HSP90 Inhibitor AT13387 for Treatment of Advanced Solid Tumors With Expansion in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, Peritoneal Cancer or Recurrent Triple-Negative Breast Cancer

This phase I trial studies the side effects and best dose of talazoparib and heat shock protein (HSP)90 inhibitor AT13387 when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or ovarian, fallopian tube, primary peritoneal, or hormone negative breast cancer that have come back after a period of improvement (recurrent). Talazoparib and HSp90 inhibitor AT13387 may stop the growth of tumor cells by blocking some enzymes that are need for cell growth. HSp90 inhibitor AT1338 may also help talazoparib work better by making tumor cells more sensitive to the drug.

Study Overview

• Status: Withdrawn
• Conditions: Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Triple-Negative Breast Carcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Adult Solid Neoplasm; Fallopian Tube Serous Neoplasm; Ovarian Serous Tumor
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Talazoparib; Drug: Hsp90 Inhibitor AT13387

Detailed Description

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTDs) of BMN673 (talazoparib) and AT13387 (HSP90 Inhibitor AT13387) administered in combination in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To identify the dose-limiting toxicity (DLT) and other toxicities associated with BMN673 and AT13387 administered in combination as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0.

II. To determine the recommended phase 2 doses (RP2D) of the combination of BMN673 and AT13387.

III. To determine the plasma pharmacokinetics of BMN673 and AT13387. IV. To document anti-tumor activity of the combination of BMN673 and AT13387 as assessed by (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression free survival (PFS).

OUTLINE: This is a dose-escalation study.

Patients receive talazoparib orally (PO) once daily (QD) on days 1-7 (course 0). Beginning in course 1, patients receive talazoparib PO QD on days 1-28 and HSP90 inhibitor AT13387 intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for up to 2 years.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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 expansion cohort, participants must have histologically or cytologically confirmed diagnosis of either: i) ovarian, fallopian tube, or primary peritoneal cancer of high grade serous histology which has recurred despite standard therapy or ii) triple-negative breast cancer which has recurred despite standard therapy
• There is no line limit for the dose escalation cohort and the dose expansion cohort
• 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 breast cancer 1/2 (BRCA1/2) germline mutation carriers
• There must be availability of a formalin-fixed, paraffin-embedded tumor specimen with adequate viable tumor tissue
• Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 3,000/mcL
• Hemoglobin >= 9 g/dL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) = < 2.5 × institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Left ventricular ejection fraction > 50% on echocardiography or multigated acquisition (ECHO/MUGA) scan
• Corrected QT (QTc) =< 450 ms
• Any clinically significant electrolyte imbalance, particularly hypokalemia and hypomagnesemia, should be corrected before treatment
• Have undergone clearance after baseline ophthalmologic exam (at least fundoscopic exam, visual acuity, intraocular pressure, assessment of visual fields and measurement of color vision)
• For the expansion cohort only: measurable disease by RECIST v1.1 with at least one measurable target lesion
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of BMN 673 and/or AT13387 administration
• Patients must be able to swallow pills and have no significant impairment in gastrointestinal absorption
• Three biopsies, one pretreatment, one after BMN673 alone and one after one of the combinations of BMN673/AT13387 will be voluntary in the expansion and dose escalation cohorts; however, biopsies will be required in at least 8 patients of the 20 patients to be enrolled in the expansion cohort
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• 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 brain metastases should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to BMN 673 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; breastfeeding should be discontinued if the mother is treated with BMN 673 or AT13387
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Known history of 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (talazoparib and Hsp90 inhibitor AT13387); Patients receive talazoparib PO QD on days 1-7 (course 0). Beginning in course 1, patients receive talazoparib PO QD on days 1-28 and HSP90 inhibitor AT13387 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Talazoparib; Given PO; Other Names: BMN 673; BMN-673; Drug: Hsp90 Inhibitor AT13387; Given IV; Other Names: AT13387

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD based on the dose-limiting toxicity based on the National Cancer Institute (NCI) CTCAE v. 4.0	DLT defined as non-hematologic and hematologic toxicities experienced during course 0 and the first course (i.e. first 4 weeks) of treatment.	35 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events as assessed by NCI CTCAE v. 4.0		30 days post-treatment
Pharmacokinetic (PK) parameters of talazoparib and HSP90 inhibitor AT13387	Pearson correlation coefficients, presented with 95% confidence intervals, will be used to investigate the association of the percent change heat shock protein 90 and poly(adenosine diphosphate-ribose) polymerase 1 activities with PK parameters, including maximum concentration observed and area under the curve.	Baseline, at 1, 2, 4 and 8 hours of day 1 (course 0), baseline of days 1, 8, and 15 of course 1, and at 1, 2, 4, and 8 hours post-dosing on day 8 and 15 of course 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in BRCA1 foci expression in tumor tissue via IHC	Paired t-tests will be used to compare BRCA1 foci formation following BMN673/AT13387.	Baseline to day 15 of course 1
Change in BRCA1 foci expression in tumor tissue via immunohistochmestry (IHC)	Paired t-tests will be used to compare BRCA1 foci formation following BMN673.	Baseline to day 7 of course 0
Change in heat shock protein 70 (HSPT70) expression	Changes in parameters of HSP70 activities that occur post-treatment will be summarized using descriptive statistics.	Day 7 (course 0) to day 15 (course 1)
Change in RAD51 foci expression in tumor tissue via IHC	Paired t-tests will be used to compare RAD51 foci formation following BMN673/AT13387.	Baseline to day 15 of course 1
Change in RAD51 recombinase (RAD51) foci expression in tumor tissue via IHC	Paired t-tests will be used to compare RAD51 foci formation following BMN673.	Baseline to day 7 of course 0

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Panagiotis Konstantinopoulos, Dana-Farber - Harvard Cancer Center LAO

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Anticipated): March 1, 2019

Study Registration Dates

• First Submitted: December 9, 2015
• First Submitted That Met QC Criteria: December 9, 2015
• First Posted (Estimate): December 11, 2015

Study Record Updates

• Last Update Posted (Estimate): July 26, 2016
• Last Update Submitted That Met QC Criteria: July 22, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Breast Diseases; Cystadenocarcinoma; Neoplasms, Cystic, Mucinous, and Serous; Neoplasms; Breast Neoplasms; Carcinoma; Recurrence; Adenocarcinoma; Cystadenocarcinoma, Serous; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: NCI-2015-02063 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA006516 (U.S. NIH Grant/Contract); UM1CA186709 (U.S. NIH Grant/Contract); 9896 (Other Identifier: CTEP)