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).
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.
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 follow up at 30 days and then every 12 weeks thereafter.
- 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 >= 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
- Life expectancy of greater than 3 months
- Pulmonary function tests forced vital capacity (FVC) of > 70%, carbon monoxide diffusing capability (DLCO) of > 60%
- 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
- Creatinine =< 1.5 x ULN OR 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
- 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)
- Cohort C: Eligibility 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
- 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
- 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 (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)
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