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Talazoparib, Carboplatin, and Paclitaxel in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02317874
Recruitment Status : Recruiting
First Posted : December 17, 2014
Last Update Posted : November 7, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
This phase I trial studies the side effects and best dose of talazoparib when given together with carboplatin and paclitaxel in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving talazoparib with carboplatin and paclitaxel may kill more tumor cells.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm BRCA Rearrangement BRCA1 Gene Mutation BRCA2 Gene Mutation Deleterious BRCA1 Gene Mutation Deleterious BRCA2 Gene Mutation Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Drug: Carboplatin Other: Laboratory Biomarker Analysis Drug: Paclitaxel Other: Pharmacological Study Drug: Talazoparib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of talazoparib (BMN 673) seven day schedule in combination with carboplatin and paclitaxel.

II. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BMN 673 three day schedule in combination with carboplatin and paclitaxel.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity of BMN 673 in combination with carboplatin and paclitaxel.

II. To determine whether the pharmacokinetic parameters of BMN 673 when given in combination with carboplatin and paclitaxel correlate with thrombocytopenia.

III. To observe and record anti-tumor activity of BMN 673 alone after the combination with carboplatin, paclitaxel and BMN673.

IV. To observe the safety and tolerability of BMN 673 in combination with paclitaxel and carboplatin and BMN 673 alone after the combination therapy.

TERTIARY OBJECTIVES:

I. To serially evaluate pharmacokinetic and pharmacodynamics parameters and use indirect pharmacokinetic/pharmacodynamics models to correlate with tumor response and resistance to the combination BMN 673, carboplatin, and paclitaxel therapy.

II. To explore mechanisms of resistance to the combination of BMN 673 with carboplatin and paclitaxel.

OUTLINE: This is a dose-escalation study of talazoparib. Patients are assigned to 1 of 2 dosing schedules.

SCHEDULE A: Patients receive talazoparib orally (PO) once daily (QD) on days 1-7, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity.

SCHEDULE B: Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity.

At any time after 4-6 courses of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 4 weeks.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of BMN 673 in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumors
Actual Study Start Date : July 24, 2015
Estimated Primary Completion Date : November 22, 2017
Estimated Study Completion Date : November 22, 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Schedule A (7-day talazoparib, paclitaxel, carboplatin)

Patients receive talazoparib PO QD on days 1-7, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity.

At any time after 4-6 courses of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
Other: Pharmacological Study
Correlative studies
Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673
Experimental: Schedule B (3-day talazoparib, paclitaxel, carboplatin)

Patients receive talazoparib PO QD on days 1-3, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4-6 courses in the absence of disease progression or unacceptable toxicity.

At any time after 4-6 courses of treatment, patients may continue combination study therapy with talazoparib, carboplatin, and paclitaxel, talazoparib and carboplatin, talazoparib alone (continuous dosing), or observation without therapy at the discretion of the treating physician.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
Other: Pharmacological Study
Correlative studies
Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673


Outcome Measures

Primary Outcome Measures :
  1. Maximum tolerated dose and recommended phase 2 dose of talazoparib seven day schedule [ Time Frame: 21 days ]
    Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, Common Terminology Criteria for Adverse Events grade, whether the event is serious, frequency, and outcom

  2. Maximum tolerated dose and recommended phase 2 dose of talazoparib three day schedule [ Time Frame: 21 days ]
    Defined as the highest safely tolerated dose where 0/6 or 1/6 (less than 33%) patients experience a dose-limiting toxicity and two or more patients have experienced a dose-limiting toxicity at the next higher dose level. Adverse events will be evaluated by type and severity using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Adverse events data collection include adverse event diagnosis, date of onset and resolution, whether the event is ongoing, Common Terminology Criteria for Adverse Events grade, whether the event is serious, frequency, and outcom


Secondary Outcome Measures :
  1. Anti-tumor response (as determined by Response Evaluation Criteria in Solid Tumors criteria) [ Time Frame: Up to 4 weeks after last dose of treatment ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease, stratified by treatment schedule. 90% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed for dose levels with 6 or more patients. Exact logistic regression analysis will be performed to evaluate the dose-response relationship. Chi-square or Fisher's exact test will be used to compare responses between treatment schedules.

  2. Incidence of toxicity, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [ Time Frame: Up to 4 weeks after last dose of treatment ]
    Toxicities observed will be summarized in terms of types and severities for each schedule and dose level separately. The number and severity of toxicity incidents will be analyzed descriptively in tabular format. Comparisons between dose level arms will be performed using Fisher's exact test. Ninety percent confidence intervals for dose-limiting toxicity rates will be constructed for dose levels with 6 or more patients.

  3. Pharmacokinetic parameters (area under the curve and concentration) in plasma samples [ Time Frame: Pre-dose and 4 hours after talazoparib administration on days 1 and 3 or 7 (depending on assigned schedule) of course 1 and 0 and 4 hours on day 1 of all subsequent courses ]
    All pharmacokinetic parameters will be summarized by treatment schedule dose level using standard descriptive statistics: means, medians, ranges, and standard deviations (if numbers and distribution permit). The Jonckheere-Terpstra trend test will be performed to determine the significance of the association between increasing dose level and each of the pharmacokinetic parameters within each treatment schedule. A Spearman rank correlation analysis will be performed to determine the relationship between actual dose administered and the pharmacokinetic parameters.


Other Outcome Measures:
  1. Changes in mutation status [ Time Frame: Baseline to time of progression (up to 4 weeks after last dose of treatment) ]
    The number and frequency of mutation status changes from the baseline biopsy assessment to the biopsy obtained at the time of progression will be summarized in tabular format. The frequency of mutation status changes will be analyzed using a paired t-test or nonparametric Wilcoxon Signed Rank test. A negative binomial regression model will be utilized to account for the dose effect. The presence of individual mutations will be compared between the baseline and time of progression assessment using a paired McNemar's test. The Benjamini-Hochberg method will also be utilized.

  2. Changes in peripheral blood mononuclear cell levels [ Time Frame: Course 1 day 1 to course 2 day 1 ]
    Changes in peripheral blood mononuclear cell levels from the course 1, day 1 (prior to first talazoparib dose) assessment to the course 1, day 3 or 7 and course 2, day 1 assessments will be evaluated using a two-sample t-test.

  3. Maximum concentration levels from plasma samples [ Time Frame: Pre-dose, 2 hours, and 4 hours after talazoparib administration on days 1 and 3 or 7 (depending on assigned schedule) of course 1 and day 1 of course 2 ]
    Maximum concentration levels will be summarized in terms of means, standard deviations and ranges. Linear mixed effects modeling with subject specific random effects will be performed to evaluate maximum concentration and plasma concentration collected on day 1 and day 3 predict changes in peripheral blood mononuclear cells. Furthermore, the empirical Bayesian approach will be utilized to incorporate pharmacokinetic data from other phase I studies of the agent to construct a pharmacokinetic population model.


Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Patients must have histologically confirmed solid malignancy (excluding lymphoma) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective, and for which: a) there is reasonable expectation of response to the combination of carboplatin/paclitaxel OR b) breast cancer (BRCA) 1/2 germline mutation is present; results from Myriad will be acceptable; if testing for BRCA 1 and 2 germline mutations is done through another organization, a report from a genetics consult with a qualified medical professional confirming that the laboratory results show a recognized germline deleterious BRCA 1 or 2 mutation or rearrangement is required; if the latter cannot be obtained, principal investigator (PI) or study chair review of the lab results and confirmation of BRCA mutation or rearrangement will be required OR c) BRCA 1/2 somatic mutation previously identified using a Clinical Laboratory Improvement Amendments (CLIA) certified assay
  • Patients must have measurable or evaluable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Absolute neutrophil count >= 1,500/mcL
  • Hemoglobin >= 9 g/dL
  • Platelets >= 150,000/mcL
  • Total bilirubin =< 1.25 x institutional upper limit of normal (ULN), with the exception of < 2.9 mg/dL for patients with Gilbert's disease
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN; =< 5 x ULN in setting of metastatic liver disease
  • Creatinine =< 1.5 x upper limit of normal OR creatinine clearance >= 50 mL/min
  • Ability to take oral medications
  • Patients with central nervous system (CNS) metastases must be stable after therapy for CNS metastases (such as surgery, radiotherapy or stereotactic radiosurgery) for at least 3 months and must be off steroid treatment for 2 weeks prior to study enrollment
  • 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 administration
  • 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) or targeted therapies within 2 weeks prior to entering the study or those who have not recovered (=< grade 1) from adverse events due to agents administered with the exception of any grade of alopecia
  • No prior carboplatin unless given in neoadjuvant/adjuvant setting for curative intent and more than 6 months have elapsed since last carboplatin dose; in the case of relapsed ovarian cancer, patients are eligible if more than 6 months have elapsed since last carboplatin dose
  • Patients who are receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to BMN 673 or other agents used in study
  • Peripheral neuropathy of severity greater than grade 1
  • The following medications are contraindicated or must be used with caution

    • Contraindicated:

      • Cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) strong and moderate inhibitors
      • CYP2C8 inducers
      • Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) strong and moderate inhibitors
      • CYP3A4 inducers
      • CYP3A4 sensitive substrates
    • Exclusions: the following supportive care medications will be allowed: dexamethasone, aprepitant, fosaprepitant, and ondansetron; oral pain medications such as hydrocodone, oxycodone taken on an as needed basis are also permitted; transdermal products designed for systemic delivery must be assessed for interaction potential; topical products not designed to provide systemic delivery (including inhaled products, ophthalmologic products and transvaginal preparations) do not need to be considered since they do not have appreciable systemic absorption
    • Other contraindicated medications (per above) are not allowed unless close monitoring with labs or drug levels with dose adjustments is feasible; patients taking these concurrent medications are ineligible unless they can discontinue or switched to alternative medications prior to initiation of the study drug (at least 5 half-lives)
    • Use with caution:

      • CYP2C8 sensitive substrates
      • CYP2C8 weak inhibitors
      • CYP3A4 non-sensitive substrates
      • CYP3A4 weak inhibitors
    • These agents may be permitted if discontinuation is not feasible and no acceptable alternatives are available as determined by the treating physician; however, caution should be used; consider monitoring with labs or drug levels and dose adjustments of the medication
  • 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
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • No clinically significant bleeding (i.e. gastrointestinal [GI] bleed, intracranial bleeding) within 6 months or major surgery within 4 weeks; minor surgeries (i.e. port placement, cataract surgery) are allowed within 2 weeks
  • Anticoagulation and anti-platelet therapies are not permitted (this includes Coumadin, low molecular weight heparins, factor Xa inhibitors, aspirin and non-steroidal anti-inflammatory drug [NSAIDS] or other medicines with similar effects)
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02317874


Locations
United States, New Jersey
Rutgers Cancer Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Nancy Chan    732-235-8675      
Principal Investigator: Nancy Chan         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Robert Wesolowski    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Robert Wesolowski         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Kari B. Wisinski    800-622-8922      
Principal Investigator: Kari B. Wisinski         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Kari Wisinski Rutgers University - Cancer Institute of New Jersey LAO
More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02317874     History of Changes
Other Study ID Numbers: NCI-2014-02474
NCI-2014-02474 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI 9782
9782 ( Other Identifier: Rutgers University - Cancer Institute of New Jersey LAO )
9782 ( Other Identifier: CTEP )
UM1CA186716 ( U.S. NIH Grant/Contract )
First Posted: December 17, 2014    Key Record Dates
Last Update Posted: November 7, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Neoplasms
Paclitaxel
Talazoparib
Albumin-Bound Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors