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

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ClinicalTrials.gov Identifier: NCT02627443
Recruitment Status : Recruiting
First Posted : December 11, 2015
Last Update Posted : February 7, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE December 9, 2015
First Posted Date  ICMJE December 11, 2015
Last Update Posted Date February 7, 2020
Actual Study Start Date  ICMJE November 4, 2016
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
  • Maximum tolerated dose (MTD) (phase I dose escalation) [ Time Frame: Up to 28 days ]
    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.
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Original Primary Outcome Measures  ICMJE
 (submitted: December 9, 2015)
PFS according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria [ Time Frame: Time from randomization to the first of either disease progression or death from any cause, assessed up to 3 years ]
The one-sided log-rank test will be used to compare PFS between the 2 treatment arms.
Change History Complete list of historical versions of study NCT02627443 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
  • Confirmed response rate [ Time Frame: Up to 3 years ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
  • Overall survival (OS) [ Time Frame: From study entry to death from any cause, assessed up to 3 years ]
    OS will be estimated using the Kaplan-Meier method.
  • 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 ]
    The duration of confirmed responses will be assessed using the Kaplan-Meier method.
  • Progression free survival (PFS) [ Time Frame: From registration to the first of either disease progression or death from any cause, up to 3 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2015)
  • Confirmed response rate per RECIST 1.1 criteria [ Time Frame: Up to 3 years ]
    The proportion of patients with a confirmed response will be calculated and compared between the 2 arms using a Chi-square or Fisher's exact test. The 95% confidence intervals will also be provided.
  • Incidence of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]
    The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. Comparisons between arms will be made by using either the Chi-square or Fisher's exact test.
  • OS [ Time Frame: Time from study entry to death from any cause, assessed up to 3 years ]
    OS will be estimated using the Kaplan-Meier method, and the log-rank test will be used to compare the 2 treatment arms.
Current Other Pre-specified Outcome Measures
 (submitted: October 7, 2019)
  • Changes in the frequency of marker inhibition [ Time Frame: Baseline to up to 3 years ]
    Semi-quantitative data will be used to compare the data between the treatment arms using boxplots and descriptive statistics.
  • Correlation between deoxyribonucleic acid (DNA) damage markers and mutation data with clinical endpoints (i.e. response, PFS, OS) [ Time Frame: Up to 3 years ]
    Statistical and graphical techniques will be used to explore these relationships. For time-to-event endpoints, we will use Cox proportional hazards models, and for response data we will use Logistic regression models. In addition, we will use Fisher's exact tests to test the association between categorical marker data and response.
Original Other Pre-specified Outcome Measures
 (submitted: December 9, 2015)
Changes in the frequency of marker inhibition [ Time Frame: Baseline to up to 3 years ]
Semi-quantitative data will be used to compare the data between the treatment arms using boxplots and descriptive statistics.
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • High Grade Ovarian Serous Adenocarcinoma
  • Metastatic Fallopian Tube Carcinoma
  • Metastatic Ovarian Carcinoma
  • Metastatic Primary Peritoneal Carcinoma
  • 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
Intervention  ICMJE
  • Drug: ATR Kinase Inhibitor M6620
    Given IV
    Other Names:
    • M 6620
    • M6620
    • VX-970
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carboplatinum
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Drug: Gemcitabine
    Given IV
    Other Names:
    • dFdC
    • dFdCyd
    • Difluorodeoxycytidine
  • Drug: Gemcitabine Hydrochloride
    Given IV
    Other Names:
    • dFdCyd
    • Difluorodeoxycytidine Hydrochloride
    • FF 10832
    • FF-10832
    • FF10832
    • Gemcitabine HCI
    • Gemzar
    • LY-188011
    • LY188011
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
Study Arms  ICMJE Experimental: Treatment (carboplatin, gemcitabine hydrochloride, VX-970)
Patients 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.
Interventions:
  • Drug: ATR Kinase Inhibitor M6620
  • Drug: Carboplatin
  • Drug: Gemcitabine
  • Drug: Gemcitabine Hydrochloride
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 7, 2019)
31
Original Estimated Enrollment  ICMJE
 (submitted: December 9, 2015)
117
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date November 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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), at cycle 1 day 2 and at cycle 2 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

    • Note: The effects of M6620 (VX-970) on the developing human fetus are unknown. For this reason and because deoxyribonucleic acid (DNA)-damage response (DDR) inhibitors as well as other therapeutic agents used in this trial may have teratogenic 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • 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. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • 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 because M6620 (VX-970) as a DNA-damage response (DDR) inhibitor may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M6620 (VX-970), 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02627443
Other Study ID Numbers  ICMJE NCI-2015-02064
NCI-2015-02064 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1563
9948 ( Other Identifier: Mayo Clinic Cancer Center LAO )
9948 ( Other Identifier: CTEP )
N01CM00099 ( U.S. NIH Grant/Contract )
P30CA015083 ( U.S. NIH Grant/Contract )
UM1CA186686 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Andrea E Wahner Hendrickson Mayo Clinic Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP