Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02627443
Recruitment Status : Recruiting
First Posted : December 11, 2015
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
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 Drug: ATR Kinase Inhibitor M6620 Drug: Carboplatin Drug: Gemcitabine Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1 Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 31 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 4, 2016
Estimated Primary Completion Date : November 30, 2020


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. Confirmed response rate [ Time Frame: Up to 3 years ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

  2. 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.

  3. 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.

  4. 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.


Other Outcome Measures:
  1. 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.

  2. 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.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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), 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

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): NCT02627443


Locations
Layout table for location information
United States, Arizona
Mayo Clinic Hospital Recruiting
Phoenix, Arizona, United States, 85054
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Bradley R. Corr         
United States, Florida
University of Florida Health Science Center - Gainesville Recruiting
Gainesville, Florida, United States, 32610
Contact: Site Public Contact    352-273-8010    cancer-center@ufl.edu   
Principal Investigator: Merry J. Markham         
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Rachel W. Miller         
United States, Michigan
Wayne State University/Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Site Public Contact    313-576-9790    ctoadmin@karmanos.org   
Principal Investigator: Ira S. Winer         
Weisberg Cancer Treatment Center Recruiting
Farmington Hills, Michigan, United States, 48334
Contact: Site Public Contact    313-576-9790    ctoadmin@karmanos.org   
Principal Investigator: Ira S. Winer         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Site Public Contact    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Premal H. Thaker         
United States, New Jersey
Rutgers Cancer Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Site Public Contact    732-235-8675      
Principal Investigator: Eugenia Girda         
United States, Pennsylvania
Thomas Jefferson University Hospital Active, not recruiting
Philadelphia, Pennsylvania, United States, 19107
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: Sarah E. Taylor         
United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Site Public Contact    434-243-6303    PAS9E@virginia.edu   
Principal Investigator: Linda R. Duska         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Andrea E Wahner Hendrickson Mayo Clinic Cancer Center LAO

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02627443    
Other Study ID Numbers: 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 )
First Posted: December 11, 2015    Key Record Dates
Last Update Posted: January 22, 2020
Last Verified: October 2019
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Adenocarcinoma
Ovarian Neoplasms
Fallopian Tube Neoplasms
Carcinoma, Ovarian Epithelial
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
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
Gemcitabine
Carboplatin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors