Clinical Trials /

Carboplatin, Gemcitabine Hydrochloride, and ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT02627443

Description:

This phase I/II trial studies the side effects and best dose of gemcitabine hydrochloride and ATR kinase inhibitor VX-970 and how well they work with carboplatin in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as carboplatin and gemcitabine hydrochloride, 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. ATR kinase inhibitor VX-970 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ATR kinase inhibitor VX-970 with chemotherapy (carboplatin and gemcitabine hydrochloride) may work better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer compared to chemotherapy alone.

Related Conditions:
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinoma
  • Primary Peritoneal Endometrioid Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Carboplatin, Gemcitabine Hydrochloride, and ATR Kinase Inhibitor VX-970 in Treating Patients With Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
  • Official Title: Phase 1 Dose Escalation and Expansion Cohort of Carboplatin and Gemcitabine With or Without M6620 (VX-970) in First or Second Recurrence Platinum-Sensitive Epithelial Ovarian, Peritoneal, and Fallopian Tube Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-02064
  • SECONDARY ID: NCI-2015-02064
  • SECONDARY ID: MC1563
  • SECONDARY ID: 9948
  • SECONDARY ID: 9948
  • SECONDARY ID: N01CM00099
  • SECONDARY ID: P30CA015083
  • SECONDARY ID: UM1CA186686
  • NCT ID: NCT02627443

Conditions

  • High Grade Ovarian Serous Adenocarcinoma
  • Ovarian Endometrioid Tumor
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Stage IV Fallopian Tube Cancer AJCC v6 and v7
  • Stage IV Ovarian Cancer AJCC v6 and v7
  • Stage IV Primary Peritoneal Cancer AJCC v7

Interventions

DrugSynonymsArms
ATR Kinase Inhibitor M6620M 6620, M6620, VX-970Treatment (carboplatin, gemcitabine hydrochloride, VX-970)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (carboplatin, gemcitabine hydrochloride, VX-970)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (carboplatin, gemcitabine hydrochloride, VX-970)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Treatment (carboplatin, gemcitabine hydrochloride, VX-970)

Purpose

This phase I/II trial studies the side effects and best dose of gemcitabine hydrochloride and ATR kinase inhibitor VX-970 and how well they work with carboplatin in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent) and has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as carboplatin and gemcitabine hydrochloride, 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. ATR kinase inhibitor VX-970 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving ATR kinase inhibitor VX-970 with chemotherapy (carboplatin and gemcitabine hydrochloride) may work better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer compared to chemotherapy alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess safety and tolerability of the combination therapy carboplatin, gemcitabine
      (gemcitabine hydrochloride) and M6620 (VX-970) (rad3-related [ATR] kinase inhibitor VX-970)
      in adult women with platinum sensitive recurrent high grade serous or high grade endometrioid
      ovarian, primary peritoneal or fallopian tube cancer. (Phase I Dose Escalation/Safety
      Lead-in) II. Determine the dose of the triple therapy to be used in the dose expansion cohort
      of the study. (Phase I Dose Escalation/Safety Lead-in) III. Confirm the safety at the maximum
      tolerated dose (MTD) for the addition of M6620 (VX-970) to carboplatin and gemcitabine in
      first or second recurrence of platinum sensitive high grade serous or endometrioid ovarian,
      primary peritoneal or fallopian tube carcinoma. (Expansion Cohort)

      SECONDARY OBJECTIVES:

      I. To determine if the MTD for the combination of carboplatin, gemcitabine and M6620 (VX-970)
      improves the confirmed response rate in adult women with platinum sensitive recurrent high
      grade serous or high grade endometrioid ovarian, primary peritoneal or fallopian tube cancer.

      II. To determine the impact of the MTD on overall survival (OS), duration of response, and
      progression-free survival (PFS).

      INTEGRATED CORRELATIVE STUDY OBJECTIVES:

      I. Collection of specimens for biomarker studies to provide preliminary proof of mechanism.
      Assess, in an exploratory fashion, whether the combination of gemcitabine and carboplatin
      activates the ATR/CHK1 pathway at achievable concentrations and also whether M6620 inhibits
      the activated pathway.

      II. To determine whether increased deoxyribonucleic acid (DNA) damage as assessed by two
      different multiplex assays correlates with response to combination therapy with M6620
      (VX-970).

      III. To determine whether mutations in homologous recombination repair genes correlate with
      response to combination therapy with M6620 (VX-970).

      IV. To ascertain modulation of ATR autophosphorylation and other pharmacodynamic readouts for
      ATR inhibition by M6620 (VX-970).

      OUTLINE: This is a phase I, dose-escalation study of gemcitabine hydrochloride and ATR kinase
      inhibitor VX-970 followed by a phase II study.

      Patients receive carboplatin intravenously (IV) over 30 minutes on day 1, gemcitabine
      hydrochloride IV over 30 minutes on days 1 and 8, and ATR kinase inhibitor VX-970 IV over 60
      minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (carboplatin, gemcitabine hydrochloride, VX-970)ExperimentalPatients receive carboplatin IV over 30 minutes on day 1, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and ATR kinase inhibitor VX-970 IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • ATR Kinase Inhibitor M6620
  • Carboplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed high grade serous or endometrioid ovarian, peritoneal or
             fallopian tube malignancy that is metastatic and for which curative measures do not
             exist; the histology can be confirmed from tissue that was taken at the time of
             diagnosis; a biopsy at the time of recurrence prior to enrollment on study is not
             required

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
             conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
             scan, magnetic resonance imaging (MRI), or calipers by clinical exam

          -  Patients enrolled in the expansion cohort will be required to have archival tumor
             tissue available for analysis and be willing to have a tumor biopsy at baseline (after
             registration and prior to starting study treatment) and at cycle 1 day 2; patients
             must have platinum sensitive disease and be in their first or second platinum
             sensitive recurrence; platinum sensitive disease is defined as recurrence that
             occurred greater than six months after completion of their last line of platinum based
             therapy; no non-platinum regimens allowed; prior therapy with PARP inhibitors as well
             as bevacizumab is allowed

          -  No more than two prior platinum based regimens; one regimen is defined as the interval
             of treatment from start of platinum based doublet to finish of that treatment course
             for the initial therapy or for the recurrent disease episode; if the nonplatinum agent
             is altered due to any reason other than disease progression, it counts as one regimen;
             for example, if a patient started on carboplatin and paclitaxel but developed a taxol
             reaction and was switched to carboplatin and Abraxane, this counts as one prior
             regimen

          -  Children are excluded from this study, but will be eligible for future pediatric
             trials

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Life expectancy of greater than 6 months

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count (ANC) >= 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 x institutional upper limit of normal (ULN)

          -  Creatinine within normal institutional limits OR creatinine clearance >= 50
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Negative serum pregnancy test result for females of child bearing potential

          -  Women of child-bearing potential must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry, for the duration of
             study participation, and 6 months after completion of M6620 (VX-970) administration;
             should a woman become pregnant or suspect she is pregnant while she is participating
             in this study, she should inform her treating physician immediately

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with platinum resistant disease or platinum sensitive disease that is past
             the first or second recurrence

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
             the study or those who have not recovered from adverse events due to agents
             administered more than 4 weeks earlier, excluding alopecia; patients with treatment
             related effects, such as peripheral neuropathy, that are grade 1 or less are eligible

          -  Prior exposure to gemcitabine

          -  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 M6620 (VX-970), carboplatin, gemcitabine or to these specific compounds

          -  M6620 (VX-970) is primarily metabolized by CYP3A4; therefore, concomitant
             administration with strong inhibitors or inducers of CYP3A4 should be avoided

          -  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 M6620 (VX-970); these potential risks also apply to the
             other agents used in this study, such as carboplatin and gemcitabine

          -  Patients with Li Fraumeni syndrome are excluded from the study as M6620 (VX-970) is a
             DDR inhibitor

          -  Addition of bevacizumab to the treatment in this study is not allowed; if the treating
             physician feels that the addition of bevacizumab is in the best interest of the
             patient, the patient should be treated with an FDA approved regimen outside of the
             present study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (phase I dose escalation)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD in this study will be defined as the highest safely tolerated dose, up to a maximum of dose level 4, where at most 1 out of six patients experience a dose limiting toxicity (DLT) with the next higher dose having at least 2 DLTs in 3 or more patients. Will be reported descriptively.

Secondary Outcome Measures

Measure:Confirmed response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Measure:Overall survival (OS)
Time Frame:From study entry to death from any cause, assessed up to 3 years
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method.
Measure:Duration of response
Time Frame:From first documented date of confirmed response (complete response [CR] or partial response [PR]), to the date at which progression is first documented, up to 3 years
Safety Issue:
Description:The duration of confirmed responses will be assessed using the Kaplan-Meier method.
Measure:Progression free survival (PFS)
Time Frame:From registration to the first of either disease progression or death from any cause, up to 3 years
Safety Issue:
Description:Disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. PFS will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated