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Mirvetuximab Soravtansine and Gemcitabine Hydrochloride in Treating Patients With FRa-Positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial, or Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT02996825
Recruitment Status : Recruiting
First Posted : December 19, 2016
Last Update Posted : October 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This phase I trial studies the side effects and best dose of mirvetuximab soravtansine and gemcitabine hydrochloride in treating patients with folate receptor (FR) alpha-positive ovarian, primary peritoneal, fallopian tube, endometrial, or triple negative breast cancer that has come back. Monoclonal antibodies, such as mirvetuximab soravtansine, may interfere with the ability of tumor cells to grow and spread. Drugs used in the chemotherapy, such as 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. Giving mirvetuximab soravtansine and gemcitabine may work better in treating patients with FRalpha-positive ovarian, primary peritoneal, fallopian tube, endometrial, or triple negative breast cancer.

Condition or disease Intervention/treatment Phase
Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor Negative Recurrent Breast Carcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Recurrent Uterine Corpus Carcinoma Triple-Negative Breast Carcinoma Folate Receptor Alpha Positive Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Biological: Mirvetuximab Soravtansine Other: Pharmacological Study Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of gemcitabine hydrochloride (gemcitabine) when given in combination with mirvetuximab soravtansine (IMGN853) to patients with FRalpha-positive recurrent ovarian, primary peritoneal, fallopian tube, endometrial cancer, or triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To explore the toxicity, response rate (RR) and progression free survival (PFS) in three expanded cohorts of heavily pre-treated FRalpha-positive a) TNBC patients; b) endometrial cancer patients; and c) ovarian, primary peritoneal, or fallopian tube cancer patients, all treated at the initial recommended phase II dose.

II. To provide additional safety data from the expanded cohorts to help inform on the RP2D for each cohort.

III. To evaluate the relationship between intratumoral levels of DM4, tumoral expression of FRalpha, and plasma concentration of DM4 at 48 and 72 hours following the first dose.

IV. To determine the pharmacokinetics (PK) of DM4 and gemcitabine when given in combination.

TERTIARY OBJECTIVES:

I. To evaluate the role of archival FRalpha expression as a substitute for the 48-72 hour (H) expression in determining intratumoral concentration of DM4.

OUTLINE: This is a dose escalation study.

Patients receive mirvetuximab soravtansine intravenously (IV) on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 3 weeks in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose-Escalation Safety and Tolerability Study of Mirvetuximab Soravtansine (IMGN853) and Gemcitabine in Patients With FRa-positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial Cancer, or Triple Negative Breast Cancer (TNBC)
Actual Study Start Date : October 2, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020


Arm Intervention/treatment
Experimental: Treatment (IMGN853, gemcitabine hydrochloride)
Patients receive mirvetuximab soravtansine IV on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 3 weeks in the absence of disease progression or unexpected toxicity.
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Mirvetuximab Soravtansine
Given IV
Other Names:
  • IMGN853
  • M9346A-sulfo-SPDB-DM4

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Recommended phase II dose assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4 [ Time Frame: Up to 3 weeks ]
    Tables will be created to summarize toxicities by dose level, cycles delivered, and total dose delivered, and side effects by dose and by cycle.


Secondary Outcome Measures :
  1. Assessment of biological correlatives assessed by biopsy [ Time Frame: Up to 2 years ]
  2. Incidence of treatment-emergent adverse events and clinically significant >= grade 3 changes assessed by CTCAE 4.0 [ Time Frame: Up to 2 years ]
    Will assess the type, severity and attribution, time to onset, and duration.

  3. PFS [ Time Frame: Time from study entry to disease progression, assessed up to 2 years ]
  4. Response assessed by Response Evaluation Criteria in Solid Tumors 1.1 [ Time Frame: Up to 2 years ]

Other Outcome Measures:
  1. FRalpha expression [ Time Frame: Day 1 ]
    FRalpha expression at baseline (in archival tissue) and in a single research biopsy (Cohort C only) at 48-72H will be correlated to intratumoral and circulating levels of DM4. Will develop a model incorporating both blood levels and FRalpha expression as predictors of DM4 intratumoral drug concentration.



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients must have one of the following pathologically documented recurrent tumor types with FRalpha positivity by the Ventana immunohistochemistry (IHC):

    • Ovarian, primary peritoneal, fallopian tube (with exclusion of low grade, clear cell or sarcomatoid histologies for ovarian cancer) >= 25% of tumor staining >= 2+ intensity
    • Endometrial >= 25% of tumor staining >= 2+ intensity
    • TNBC confirmed by medical history of HER2-negative (confirmed by IHC 0, 1+ regardless of fluorescence in situ hybridization [FISH] ratio; IHC 2+ with FISH ratio < 2.0 or HER2 gene copy < 6.0; FISH ratio of 0, indicating gene deletion; when positive and negative in situ hybridization controls are present); estrogen receptor (ER) negative (confirmed as ER expression =< 1% positive tumor nuclei); progesterone receptor (PR) negative (confirmed as PR expression =< 1% positive tumor nuclei): >= 25% of tumor staining >= 1+ intensity
  • 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 >= 10 mm and short axis for nodal lesions >= 15 mm); patients with recurrent ovarian, primary peritoneal, fallopian tube cancer may have biochemical relapse only, with baseline values of CA-125 at least 2 X upper limit of normal (ULN)
  • Treatment with targeted agents, immunotherapy, or hormones is allowed; patients are only eligible if they have received and failed, or have been intolerant to standard treatments known to confer clinical benefit
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Alkaline phosphatase =< 2.5 X institutional upper limit of normal
  • Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential must have a negative pregnancy test at screening and must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 3 months after the last dose of IMGN853 and gemcitabine
  • Patients must consent to analysis on archival tissue
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients must have resolution of toxic effect(s) of the most recent prior chemotherapy to grade 1 or less (except alopecia)
  • Cohort A: Patients with TNBC must have received no more than 4 lines of systemic cytotoxic chemotherapy; patients must have received and failed, or have been intolerant to anthracycline, taxanes, capecitabine, eribulin or other agents known to confer clinical benefit; patients are not required to fail all these agents if, in the investigator's opinion, patients would benefit from treatment on current protocol
  • Cohort B: Patients with recurrent endometrial cancer may have received up to 2 lines of cytotoxic chemotherapy (adjuvant and one line for recurrent disease, or 2 lines of chemotherapy for recurrent uterine cancer in patients who did not receive adjuvant chemotherapy); patients must have received and failed, or have been intolerant to platinum agents, taxanes, liposomal doxorubicin or other agents known to confer clinical benefit; patients are not required to fail all these agents if, in the investigator's opinion, patients would benefit from treatment on current protocol
  • Cohort C: Eligible patients must have received no more than 4 lines of systemic cytotoxic chemotherapy and must have disease resistant to platinum therapy (disease that progressed during or within six months of completing subsequent platinum therapy); primary platinum refractory patients are eligible providing they meet other eligibility criteria; in addition to platinum agents, patients must have received and failed, or have been intolerant to taxanes, liposomal doxorubicin or other agents known to confer clinical benefit; patients are not required to fail all these agents if, in the investigator's opinion, patients would benefit from treatment on current protocol
  • Cohort C: Patients in this cohort only will require a single tumor biopsy 48-72H after the first administration of IMGN853 and gemcitabine on day 1, cycle 1 of treatment, providing it is safe/feasible and confers non-significant risk to patient

Exclusion Criteria:

  • Previous treatment with gemcitabine
  • Prior treatment with FR-targeting investigational agents is not allowed
  • Patients who have had chemotherapy (including investigational cytotoxic chemotherapy), biologic agents (e.g., cytokines or antibodies) within 3 weeks (6 weeks for nitrosoureas or mitomycin C) before the first dose of study treatment
  • Patients who have received radiation within 14 days before the first dose of study treatment
  • Any other prior malignancy from which the patient has been disease free for less than 3 years, with the exception of adequately treated and basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site
  • Patients with known brain metastases
  • Serious concurrent illness or clinically-relevant active infection, including, but not limited to the following:

    • Known active hepatitis B or C
    • Known human immunodeficiency virus (HIV) infection
    • Varicella-zoster virus (shingles)
    • Cytomegalovirus infection
    • Any other known concurrent infectious disease, requiring IV antibiotics with 2 weeks of study enrollment
  • Other intercurrent illness including, but not limited to symptomatic congestive heart failure and/or QT interval > 470 for females and > 450 for males, unstable angina pectoris, cardiac arrhythmia, hemorrhagic or ischemic stroke within the last 6 months or psychiatric illness/social situations that would limit compliance with study requirements
  • History of interstitial pneumonitis
  • History of cirrhotic liver disease
  • Presence of > grade 1 peripheral neuropathy
  • Active or chronic corneal disorder, including but not limited to the following: Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal transplantation, active herpetic keratitis, and also active ocular conditions requiring on-going treatment/monitoring such as wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presence of papilledema, and acquired monocular vision
  • Major surgery within 2 months prior to enrollment or minor surgery within 7 days of the first day of treatment
  • History or evidence of thrombotic or hemorrhagic disorders within 6 months before first study treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or IMGN853
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with gemcitabine or IMGN853
  • Required used of folate-containing supplements (e.g. folate deficiency)

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): NCT02996825


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Mihaela C. Cristea, MD    800-826-4673    mcristea@coh.org   
Principal Investigator: Mihaela C. Cristea, MD         
City of Hope Rancho Cucamonga Recruiting
Rancho Cucamonga, California, United States, 91730
Contact: Valerie Estala    626-256-4673 ext 81699    vestala@coh.org   
Principal Investigator: Behnam Ebrahimi, MD         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mihaela Cristea, MD City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02996825     History of Changes
Other Study ID Numbers: 16294
NCI-2016-01913 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16294 ( Other Identifier: City of Hope Medical Center )
First Posted: December 19, 2016    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Triple Negative Breast Neoplasms
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Gemcitabine
Maytansine
Immunoconjugates
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators