PRIMARY OBJECTIVE:
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.
EXPLORATORY OBJECTIVE:
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. Cycles 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.
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) >= 50% of tumor staining >=
2+ intensity
- Endometrial >= 50% 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, determined within 14 days of registration
- Platelets >= 100 x 10^9/L, determined within 14 days of registration
- Total bilirubin =< 1.5 x upper limit of normal (ULN), determined within 14 days of
registration
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal, determined within 14 days of
registration
- Alkaline phosphatase =< 2.5 X institutional upper limit of normal, determined within
14 days of registration
- Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal, determined within 14 days of registration
- 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)
