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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

This study has been withdrawn prior to enrollment.
(Other - Protocol moved to Withdrawn)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02627430
First received: December 9, 2015
Last updated: July 22, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
Adult Solid Neoplasm Estrogen Receptor Negative Fallopian Tube Serous Neoplasm HER2/Neu Negative Ovarian Serous Adenocarcinoma Ovarian Serous Tumor Primary Peritoneal Serous Adenocarcinoma Progesterone Receptor Negative Recurrent Breast Carcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Triple-Negative Breast Carcinoma Drug: Hsp90 Inhibitor AT13387 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Talazoparib Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

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


Secondary Outcome Measures:
  • Incidence of adverse events as assessed by NCI CTCAE v. 4.0 [ Time Frame: 30 days post-treatment ]
  • Pharmacokinetic (PK) parameters of talazoparib and HSP90 inhibitor AT13387 [ Time Frame: 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 ]
    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.


Other Outcome Measures:
  • Change in BRCA1 foci expression in tumor tissue via IHC [ Time Frame: Baseline to day 15 of course 1 ]
    Paired t-tests will be used to compare BRCA1 foci formation following BMN673/AT13387.

  • Change in BRCA1 foci expression in tumor tissue via immunohistochmestry (IHC) [ Time Frame: Baseline to day 7 of course 0 ]
    Paired t-tests will be used to compare BRCA1 foci formation following BMN673.

  • Change in heat shock protein 70 (HSPT70) expression [ Time Frame: Day 7 (course 0) to day 15 (course 1) ]
    Changes in parameters of HSP70 activities that occur post-treatment will be summarized using descriptive statistics.

  • Change in RAD51 foci expression in tumor tissue via IHC [ Time Frame: Baseline to day 15 of course 1 ]
    Paired t-tests will be used to compare RAD51 foci formation following BMN673/AT13387.

  • Change in RAD51 recombinase (RAD51) foci expression in tumor tissue via IHC [ Time Frame: Baseline to day 7 of course 0 ]
    Paired t-tests will be used to compare RAD51 foci formation following BMN673.


Enrollment: 0
Study Start Date: March 2016
Estimated Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Hsp90 Inhibitor AT13387
Given IV
Other Name: AT13387
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02627430

Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Panagiotis Konstantinopoulos Dana-Farber - Harvard Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02627430     History of Changes
Other Study ID Numbers: NCI-2015-02063
NCI-2015-02063 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9896 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9896 ( Other Identifier: CTEP )
P30CA006516 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
Study First Received: December 9, 2015
Last Updated: July 22, 2016

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Adenocarcinoma
Triple Negative Breast Neoplasms
Breast Neoplasms
Ovarian Neoplasms
Fallopian Tube Neoplasms
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 21, 2017