A Phase 1, First-in-Human, Open-Label, Dose-Escalation and Expansion Study of IMGN151 (anti-FRα antibody-drug conjugate) in Adult Patients with Recurrent Endometrial Cancer and Recurrent, High-Grade Serous Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers (IMGN151)
Recruiting
18-99 years
All
Phase
N/A
10 participants needed
1 Location
Brief description of study
- To assess safety and tolerability, including dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD; if no MTD is defined) of IMGN151 when administered intravenously
- To determine recommended Phase 2 dose (RP2D) for IMGN151
- To characterize the pharmacokinetics (PK) and immunogenicity of IMGN151 -To assess ORR for IMGN151 using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) -To assess DOR for IMGN151 using RECIST v1.1
Exploratory Objectives
- To assess progression-free survival (PFS) for IMGN151 -To assess potential biomarkers of clinical and/or immunologic response to IMGN151 in blood and tumor tissue -To assess the relationship between FR expression by IHC and baseline soluble FR levels with antitumor activity -To assess CA-125 response rate based on Gynecologic Cancer Intergroup (GCIG) criteria -To assess safety and tolerability, including dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD; if no MTD is defined) of IMGN151 when administered intravenously -To determine recommended Phase 2 dose (RP2D) for IMGN151 The exploratory objective of the study is to investigate the relationship between expression levels of FR and antitumor activity of IMGN151 and whether patient selection based on FR expression is justified.
- To assess progression-free survival (PFS) for IMGN151 -To assess potential biomarkers of clinical and/or immunologic response to IMGN151 in blood and tumor tissue -To assess the relationship between FR expression by IHC and baseline soluble FR levels with antitumor activity -To assess CA-125 response rate based on Gynecologic Cancer Intergroup (GCIG) criteria -To assess safety and tolerability, including dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD; if no MTD is defined) of IMGN151 when administered intravenously -To determine recommended Phase 2 dose (RP2D) for IMGN151 The exploratory objective of the study is to investigate the relationship between expression levels of FR and antitumor activity of IMGN151 and whether patient selection based on FR expression is justified.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Medical Research
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Age: Between 18 Years - 99 Years
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Gender: All
Inclusion Criteria
1. Patients ≥ 18 years of age
2. An Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
3. Dose-Escalation Phase: A confirmed diagnosis of recurrent endometrial cancer (endometrioid or serous histology only) or high-grade serous epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Patients will have exhausted appropriate standard-of-care therapy and be appropriate for participation in a single-agent Phase 1 study in the opinion of the investigator.
4. Expansion Phase:
a. A confirmed diagnosis of recurrent endometrial cancer (endometrioid or serous histology only) or platinum-resistant, high-grade serous EOC (PROC). Patients with PROC will have had 1-4 prior lines of therapy. Platinum-resistant disease is defined as radiographic progression within 6 months (182 days) after the last dose of the most recent platinum therapy.
b. If performed previously, results of germline and/or somatic BRCA testing must be reported at study entry. Patients with tumors harboring a BRCA mutation are required to have received prior treatment with a PARP inhibitor if available locally and medically appropriate. Note that BRCA testing is not required for enrollment for patients who have not had it done previously.
c. For patients with endometrial cancer, prior checkpoint inhibitor therapy, alone or in combination, is required if available locally and medically appropriate.
Note: Progression is calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
5. Prior anticancer therapy
a. For Expansion Phase: Patients must have recurrent endometrial cancer or patients with PROC must have received 1-4 prior systemic lines of therapy.
b. Neoadjuvant and adjuvant therapies are considered 1 line of therapy.
c. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (ie, not counted independently).
d. Therapy changed due to toxicity in the absence of progression will be considered part of the same line (ie, not counted independently).
e. Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
f. For Cohort C: Prior FRα-targeting therapy and at least 1 intervening therapy prior to IMGN151 treatment is required.
6. Evaluable lesions
a. Dose-Escalation Phase: Both radiologically evaluable and nonevaluable disease is acceptable.
b. Expansion Phase: Patients must have at least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the investigator).
7. An archival tumor tissue block or slides, or a procedure to obtain a new biopsy using a low-risk, medically routine procedure for retrospective IHC confirmation of FRα status is required.
a. Expansion Phase: For patients with ovarian cancer enrolled in the prior FRα-targeting agent exposure cohort (Cohort C), in addition to providing an archival tissue from prior to receipt of prior FRα-targeting agent, patients are required to provide a second tumor tissue sample after completion of prior FRα-targeting therapy and before the start of IMGN151 treatment.
8. Completed prior therapy within the specified times below:
a. Systemic antineoplastic therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to first dose of IMGN151
b. Focal radiation completed at least 2 weeks prior to first dose of IMGN151
9. Stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia).
10. Completed any major surgery at least 4 weeks prior to first dose of IMGN151 and have recovered or stabilized from the side effects of prior surgery prior to first dose of IMGN151.
11. Adequate hematologic, liver and kidney functions defined as:
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor (G-CSF) in the prior 10 days or long-acting white blood cell growth factors in the prior 20 days
b. Platelet count ≥ 100 × 109/L (100,000/μL) without platelet transfusion in the prior 10 days
c. Hemoglobin ≥ 9.0 g/dL without packed red blood cell transfusion in the prior 10 days
d. Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 or an estimated creatinine clearance of ≥ 60 mL/min
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × ULN
f. Bilirubin ≤ 1.5 × ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 × ULN)
g. Albumin ≥ 2 g/dL
12. Willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
13. FOCBP must agree to use highly effective contraceptive method(s) while on IMGN151 and for at least 28 weeks after the last dose.
14. For FOCBP, a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 72 hours before the first dose of IMGN151 is required.
Exclusion Criteria
1. Patients with ovarian cancer with histologies including endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, as well as low-grade/borderline ovarian tumor
2. Radiation therapy of >20% of the potential bone marrow
Note: WPXRT only for endometrial cancer given in the adjuvant setting, ± vaginal cuff brachytherapy, is permitted.
3. Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE v5.0)
4. Active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as active or recurrent uveitis, uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision
5. Serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
a. Active hepatitis B or C infection (whether or not on active antiviral therapy)
b. HIV infection in patients with CD4+ T-cell (CD4+) counts < 350 cells/uL
c. Active cytomegalovirus infection
d. Active COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 testing is not mandatory for study entry, testing should follow local clinical practice guidelines and standards
e. Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to the first dose of IMGN151
Note: Testing at Screening is not required for the above infections unless clinically indicated.
6. History of multiple sclerosis or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
7. Clinically significant cardiac disease including, but not limited to, any of the following:
a. Myocardial infarction ≤ 6 months before first dose
b. Unstable angina pectoris
c. Uncontrolled congestive heart failure (New York Heart Association > class II)
d. Uncontrolled ≥ Grade 3 hypertension (per CTCAE v5.0)
e. Uncontrolled cardiac arrhythmias
f. QTc interval > 470 ms
8. History of hemorrhagic or ischemic stroke within 6 months before enrollment
9. History of cirrhotic liver disease (Child-Pugh Class B or C)
10. Evidence of pneumonitis on baseline imaging or patients with a previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonitis
11. Prior hypersensitivity to monoclonal antibodies (mAb)
12. Patients who are pregnant or breastfeeding
13. For Expansion Phase: Receipt of a prior FRα-targeting agent, with the exception of patients enrolled in the prior FRα-targeting agent, ovarian cancer cohort (Cohort C).
14. Untreated or symptomatic central nervous system metastases
Note: Patients requiring ongoing steroids for central nervous system metastases are not eligible for enrollment.
15. History of other malignancy within 3 years prior to enrollment
Note: Patients with tumors with a negligible risk for metastasis or death (eg, adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.
16. Prior known hypersensitivity reactions to study drugs and/or any of their excipients
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
Updated on
11 Sep 2024.
Study ID: 856356
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