A Phase 2 Study of Mirvetuximab Soravtansine (IMGN853) and Pembrolizumab in Endometrial Cancer (EC)

• ClinicalTrials.gov Identifier: NCT03835819
• Recruitment Status: Recruiting
• First Posted: February 11, 2019
• Last Update Posted: November 14, 2023
• Sponsor: Dana-Farber Cancer Institute
• Collaborators: ImmunoGen, Inc.; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: February 6, 2019
• First Posted Date: February 11, 2019
• Last Update Posted Date: November 14, 2023
• Actual Study Start Date: January 2, 2020
• Estimated Primary Completion Date: October 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 7, 2019)

• Objective Response Rate [ Time Frame: 6 months ]
• Progression Free Survival [ Time Frame: 6 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 7, 2019)

• Duration of response [ Time Frame: 2 years ]
• Overall Survival [ Time Frame: 2 Years ]
• Immune-related progression-free survival [ Time Frame: 2 years ]
• Immune-related progression of disease [ Time Frame: 2 Years ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 2 Study of Mirvetuximab Soravtansine (IMGN853) and Pembrolizumab in Endometrial Cancer (EC)
• Official Title: A Phase 2, Two-stage, Study of Mirvetuximab Soravtansine (IMGN853) in Combination With Pembrolizumab in Patients With Microsatellite Stable (MSS) Recurrent or Persistent Endometrial Cancer (EC)

Brief Summary

This research study is studying a drug combination as a possible treatment for endometrial cancer.

The drugs involved in this study are:

• mirvetuximab soravtansine (IMGN853)
• pembrolizumab

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved mirvetuximab soravtansine as a treatment for any disease.

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this specific disease but it has been approved for other uses.

In this research study, the investigators are studying the combination of mirvetuximab soravtansine and pembrolizumab. Pembrolizumab is an immunotherapy that activates a patient's own immune system to recognize and kill tumor cells. Pembrolizumab by itself may not be enough to kill cancer cells in all people with cancer. In this study, all patients will receive mirvetuximab soravtansine and pembrolizumab. Mirvetuximab soravtansine is an antibody-drug conjugate. That is a type of agent that attaches a chemotherapy drug to a molecule that binds a protein on the outside of cancer cells. The protein targeted by mirvetuximab soravtansine is called folate receptor-alpha (FRα). FRα is expressed on the surface of certain cancers, including endometrial cancer cells. Mirvetuximab soravtansine is expected to kill cancer cells by delivering chemotherapy to cells that have high levels of FRα. To participate in this study, a sample of your tumor was previously tested, and was found to have high levels of FRα. Mirvetuximab soravtansine also may also active immune cells and improve the response to immunotherapies like pembrolizumab.

In this study, the investigators expect to learn whether the combination of pembrolizumab and mirvetuximab soravtansine can shrink endometrial cancers or prevent their growth for at least 6 months. The investigators will also learn more about the side effects patients experience who receive this treatment. The investigators also plan to learn more about which patients are likely to benefit from this treatment

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Endometrial Cancer

Intervention

• Drug: Pembrolizumab
  Pembrolizumab is an immunotherapy that activates a patient's own immune system to recognize and kill tumor cells
• Drug: IMGN853
  Mirvetuximab soravtansine is an antibody-drug conjugate.
  Other Name: Mirvetuximab soravtansine

Study Arms

Experimental: IMGN853 + Pembrolizumab

• Pembrolizumab is administered intravenously once every 3 weeks
• IMGN853 is administered intravenously once every 3 weeks

Interventions:

• Drug: Pembrolizumab
• Drug: IMGN853

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 7, 2019): 35
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 1, 2026
• Estimated Primary Completion Date: October 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must have advanced or recurrent serous endometrial cancer. Patients with mixed histologies/tumors are eligible if the serous component is the dominant histological subtype. In addition, the tumors must be:
• microsatellite stable (MSS) as documented by either intact immunohistochemical (IHC) nuclear expression of the mismatch repair genes MSH2, MSH6, MLH1 and PMS2; or microsatelitte stable by polymerase chain reaction (PCR), next generation sequencing, or other CLIA-approved method;

AND

• FRα positive by central immunohistochemistry (IHC, Section 9.1). If archival tissue does not meet FRα criteria, a fresh biopsy tumor sample may be submitted and used to meet this criterium. If a fresh tumor biopsy cannot be done safely the patient will not be allowed to enroll on this study.

  • Participants must have measurable disease as defined by RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  • Prior therapy: Patients must have had one, but no more than three lines of chemotherapy for endometrial carcinoma.
• Prior hormonal therapy is allowed (no washout period is required after hormonal therapy) and does not count as a prior line of therapy. Hormonal therapy in combination with CDK4/6 inhibitors or mTOR or other PI3K-pathway inhibitors is allowed and does not count as a line of prior therapy.
• Prior IO therapy targeted to the PD-1/PD-L1 pathway is allowed in up to 19 patients of the total cohort.

• Patients must NOT have received prior therapy with any folate receptor ortholog agents.

  • Age 18 or greater years. Because insufficient dosing or adverse event data are currently available on the use of mirvetuximab soravtansine and pembrolizumab in participants <18 years of age, children are excluded. Endometrial cancer is rare in the pediatric population.
  • ECOG performance status 0 or 1
  • Participants must have normal organ and marrow function as defined below:
• leukocytes ≥3,000/mcL
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin ≥ 9.0 g/dL
• total bilirubin ≤ 1.5 x institutional upper limit of normal
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
• creatinine ≤ institutional upper limit of normal OR

• creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

  -Time from prior therapy:

• Systemic anti-neoplastic therapy: 5 half-lives or 4 weeks, whichever is shorter. Hormonal therapy is not considered anti-neoplastic therapy.

• Radiotherapy: wide-field radiotherapy (e.g. > 30% of marrow-bearing bones) completed at least 4 weeks, or focal radiation completed at least 2 weeks, prior to starting study treatment

  • The effects of agents used in this study on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study treatment, and for at least twelve weeks after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
  • Women of child-bearing potential must have a negative serum pregnancy test within 3 days prior to the first dose of study treatment.
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants who have had chemotherapy within 5 half-lives or 4 weeks (whichever is shorter) or radiotherapy within 2 weeks prior to entering the study. Patients completing wide-field radiotherapy (e.g. >30% of marrow-bearing bones) must not have had treatment within 4 weeks prior to entering study. Participants must have recovered from all AEs due to previous therapy to Grade 1 ≤ or baseline, except alopecia.
• Participants who are receiving any other investigational agents.
• Participants with prior exposure to IO agents targeting the PD-1/PD-L1 pathway who discontinued therapy due to treatment-related toxicity deemed to be specifically related to IO therapy.
• Required use of folate-containing supplements (e.g. folate deficiency).
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to monoclonal antibodies (including antibody drug-conjugates or checkpoint inhibitors).
• Uncontrolled intercurrent illness including, but not limited to, any of the following within 6 months of first study treatment: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled hypertension (≥ Grade 3), hypertensive crisis or hypertensive encephalopathy, uncontrolled cardiac arrhythmias, thrombotic or ischemic stroke, clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm), severe aortic stenosis, clinically significant peripheral vascular disease, or ≥ Grade 3 cardiac toxicity following prior chemotherapy, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• 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.
• Serious clinically-relevant active infection, including known HIV infection, varicella-zoster virus, cytomegalovirus infection, has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) or any other known concurrent infectious disease requiring IV antibiotics with within 2 weeks of study enrollment are ineligible because of the potential for immune side effects.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

• Current or prior use of immunosuppressive medication within 7 days prior to enrollment with the following exceptions to this exclusion criterion:

  • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
  • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, hypo-or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Pregnant or nursing women are excluded from this study because effects of agents used in this study on infants or the developing human fetus are unknown
• Presence of other malignancies unless they are considered cured by patient's oncologist

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: DFCI Clinical Trials Hotline; 877-338-7425; madeline_polak@dfci.harvard.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03835819
• Other Study ID Numbers: 18-602
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

• Current Responsible Party: Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current

Collaborators

• ImmunoGen, Inc.
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Rebecca Porter, MD, PhD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: November 2023