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An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of VX-970 in Combination With Cytotoxic Chemotherapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2016 by Vertex Pharmaceuticals Incorporated
Sponsor:
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT02157792
First received: June 1, 2014
Last updated: November 15, 2016
Last verified: October 2016
  Purpose
An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics (PK) of VX-970 in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors

Condition Intervention Phase
Advanced Solid Tumor
Drug: VX-970
Drug: Gemcitabine
Drug: Cisplatin
Drug: Etoposide
Drug: Carboplatin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of VX-970 in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors

Further study details as provided by Vertex Pharmaceuticals Incorporated:

Primary Outcome Measures:
  • Parts A, B, C1, C2, C3: Safety parameters, including adverse event (AEs), clinical laboratory values (serum chemistry, hematology, and urinalysis), vital signs, and electrocardiogram (ECG) assessments [ Time Frame: Screening through Safety Follow-up (approximately 22 weeks) ] [ Designated as safety issue: Yes ]
  • Parts C1, C2, C3: Overall Response Rate (ORR) for all subjects in Part C1 (NSCLC), ORR for subjects in Part C2 (TNBC) who are basaloid subtype and BRCA1/BRCA2 germline wild-type, ORR for all subjects in Part C3 (SCLC) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Part A: Maximum tolerated dose (MTD) of VX-970 administered in combination with cisplatin and gemcitabine and in combination with gemcitabine [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Part A: Pharmacokinetic (PK) parameter estimates of VX-970 in combination with cisplatin and gemcitabine and in combination with gemcitabine [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Part B: Maximum tolerated dose (MTD) of VX-970 in combination with cisplatin and in combination with cisplatin and etoposide [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Part B: PK parameter estimates of VX-970 in combination with cisplatin and in combination with cisplatin and etoposide [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Part B: PK parameter estimates of etoposide derived from plasma concentration-time data after coadministration with VX-970 and in the absence of VX-970 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts A, B: Objective tumor response (OR) as evaluated by Response Criteria Evaluation in Solid Tumors (RECIST) 1.1 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Part C2: Overall Response Rate in all subjects in Part C2 [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts C1, C2, C3: Progression Free Survival (PFS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts C1, C2, C3: Response Duration (RD) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts C1, C2, C3: Overall Survival (OS) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts C1, C2, C3: Clinical benefit (Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) of 6 months or greater) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Parts C1, C2, C3: PK parameter estimates of VX-970 including maximum concentrations (Cmax), area under the curve (AUC), apparent volume at steady state (Vss), clearance (CL) and terminal elimination half-life (t1/2) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 205
Study Start Date: December 2012
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A
3 + 3 dose escalation of VX-970 in combination with gemcitabine as well as gemcitabine and cisplatin
Drug: VX-970 Drug: Gemcitabine Drug: Cisplatin
Experimental: Part B
3 + 3 dose escalation study of VX-970 in combination with cisplatin as well as cisplatin and etoposide
Drug: VX-970 Drug: Cisplatin Drug: Etoposide
Experimental: Part C1
VX-970 in combination with gemcitabine administered in subjects with advanced non-small cell lung cancer (NSCLC)
Drug: VX-970 Drug: Gemcitabine
Experimental: Part C2
VX-970 in combination with cisplatin in subjects with advanced triple negative breast cancer (TNBC)
Drug: VX-970 Drug: Cisplatin
Experimental: C3
VX-970 in combination with cisplatin or carboplatin in subjects with platinum-resistant advanced small cell lung cancer (SCLC)
Drug: VX-970 Drug: Cisplatin Drug: Carboplatin

  Eligibility

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

Inclusion Criteria:

Disease status

  • Parts A and B: Histologically or cytologically confirmed advanced solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective, or for whom regimens containing gemcitabine, cisplatin, and/or etoposide might be considered, and with measurable disease according to RECIST criteria
  • Part C1:

For Pre-screening:

  • Advanced (metastatic or locally-advanced unresectable and not eligible for definitive treatment, e.g., surgery/radiotherapy), histologically confirmed non-small cell lung cancer (NSCLC)
  • Available historical tumor specimen at the time of pre-screening or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient
  • Received or did not tolerate standard approved targeted therapy, if appropriate for tumor genotype

For Screening:

  • Measurable disease according to RECIST criteria

    -Part C2:

  • Advanced (locally-advanced incurable or metastatic) histologically confirmed estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) negative breast cancer.
  • Adequate available historical tumor specimen or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient
  • Measurable disease according to RECIST criteria

    -Part C3:

  • Advanced (locally-advanced incurable or metastatic) histologically confirmed SCLC that is platinum-resistant, defined as disease progression during initial treatment with a platinum-based regimen or progression within 90 days of completion of platinum therapy. Subjects with platinum-resistant disease may receive a second-line non-platinum-based chemotherapy and subsequently be enrolled to this study. Subjects who received and are resistant to a second-line platinum-based chemotherapy may also be enrolled into the study.
  • Adequate available historical tumor specimen or willing to provide a tumor biopsy (core) if the biopsy may be considered as part of standard clinical practice for the patient
  • Measurable disease according to RECIST criteria
  • WHO performance status of 0 or 1
  • Life expectancy of ≥12 week
  • Hematological and biochemical indices within protocol specified ranges at screening.

Exclusion Criteria:

  • Radiotherapy (except for palliative reasons) endocrine therapy, immunotherapy, or chemotherapy during the previous 4 weeks (6 weeks for nitrosoureas and Mitomycin-C, and 4 weeks for investigational medicinal products) or less than 4 drug half-lives, whichever greater, before first dose of study drug.
  • Parts A and B:

    • Greater than 6 cycles of prior treatment with cisplatin and/or carboplatin.

      (a) History of prior dose reductions or dose interruptions while receiving cisplatin or carboplatin due to toxicity from the platinum or intolerance to either agent.

    • Subjects with a known history of Grade 4 thrombocytopenia or Grade 4 neutropenia while receiving prior therapy.
  • Part C1:

    • Any cytotoxic chemotherapy beyond 1 line of platinum-based chemotherapy. One additional line of non-platinum based therapy in the advanced setting

      1. Pre-screening Only*: Subjects may currently be receiving platinum-based chemotherapy in the advanced setting, or have completed 1 line of platinum-based chemotherapy and are currently receiving a second-line non-platinum-based therapy or maintenance therapy
      2. There is no restriction on prior immunotherapy or targeted therapy unless combined together with a cytotoxic agent
    • Any prior gemcitabine for the treatment of NSCLC in any setting within 6 months
    • Subjects who are known to be TP53 wild-type, unless they are determined to have ATM loss of expression during screening or pre-screening or until all the planned subjects with TP53 mutation are enrolled as determined by the medical monitor
    • Subjects with unknown TP53 mutational status will be enrolled until the group of approximately 10 subjects without TP53 mutation or until all the planned subjects with TP53 mutation are enrolled as determined by the medical monitor
  • Part C2:

    • Any prior platinum therapy in the adjuvant or neoadjuvant within 6 months of screening
    • Relapse within 3 months of completion of prior adjuvant or neoadjuvant chemotherapy
    • Any prior chemotherapy in the metastatic setting with the exception of either a taxane or an anthracycline in the first-line metastatic setting

      (a) There is no restriction on prior immunotherapy or targeted therapy in the metastatic setting unless combined together with a cytotoxic agent

    • Subjects with known BRCA1/BRCA2 germline mutations, either determined and documented prior to Screening, or determined during Screening. Subjects with unknown BRCA1/BRCA2 status may be enrolled at discretion of the sponsor
    • Subjects who are documented to be non-basaloid subtype using molecular profiling assay (e.g. PAM50 assay) prior to Screening
    • Subjects with unknown BRCA1/BRCA2 or basaloid subtype status will be enrolled until the number of enrolled subjects is approximately 40. If approximately 40 subjects have been enrolled and a minimum of 30 subjects who are basaloid positive and BRCA1/BRCA2 germline wild-type have not been enrolled, the basaloid subtype and BRCA status assay will be required at Screening to exclude subjects who are basaloid negative or have BRCA1/BRCA2 germline mutations.
  • Part C3:

    • Prior platinum-sensitive subjects, unless they progress on or within 90 days of completion of platinum-based regimen
    • There is no restriction on prior immunotherapy or targeted therapy in the metastatic setting unless combined together with a cytotoxic agent
    • During prior carboplatin therapy, requirement for dose reduction below AUC 5 mg.min/mL or discontinuation of carboplatin for toxicity or lack of tolerability.
  • Unresolved toxicity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater from previous anti-cancer therapy or radiotherapy
  • History of spinal cord compression or brain metastases, unless asymptomatic, treated, stable, and not requiring treatment with steroids for at least 4 weeks before first dose of study drug. Any history of leptomeningeal metastases.
  • Female subjects who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded. Female subjects of childbearing potential must adhere to contraception guidelines
  • Male subjects with partners of child-bearing potential must agree to adhere to contraception guidelines. Men with pregnant or lactating partners or partners who plan to become pregnant during the study or within 6 months of the last dose of study drug are excluded
  • Serious cardiac or other co-morbid disease, as specified in the protocol
  • Prior bone marrow transplant or extensive radiotherapy to greater than 15% of bone marrow
  • Part C:

    • Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin
  • Major surgery ≤2 weeks before starting study drug, or incomplete recovery from a prior major surgical procedure.
  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: NCT02157792

Contacts
Contact: Medical Monitor 617-341-6777 medicalinfo@vrtx.com

  Show 25 Study Locations
Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
  More Information

Responsible Party: Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier: NCT02157792     History of Changes
Other Study ID Numbers: VX12-970-001  2012-003126-25 
Study First Received: June 1, 2014
Last Updated: November 15, 2016
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Vertex Pharmaceuticals Incorporated:
Solid Tumor
Advanced Solid Tumor

Additional relevant MeSH terms:
Gemcitabine
Etoposide phosphate
Cisplatin
Carboplatin
Etoposide
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on December 07, 2016