| Eligibility |
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)
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