Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies

• ClinicalTrials.gov Identifier: NCT04370704
• Recruitment Status: Recruiting
• First Posted: May 1, 2020
• Last Update Posted: June 1, 2023
• Sponsor: Incyte Corporation
• Information provided by (Responsible Party): Incyte Corporation

Study Description

Brief Summary:

The study will determine Recommended Phase 2 Dose for all study drugs, based on the safety and tolerability of the following combinations: INCAGN02385 + INCAGN02390 and INCAGN02385 + INCAGN02390 + INCMGA00012.

Condition or disease	Intervention/treatment	Phase
Melanoma	Drug: INCAGN02385; Drug: INCAGN02390; Drug: INCMGA00012.	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 146 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1-2 Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies
• Actual Study Start Date: July 27, 2020
• Estimated Primary Completion Date: July 21, 2023
• Estimated Study Completion Date: August 4, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 Part 1; Part 1 will confirm the safety of INCAGN02385 and INCAGN02390 when used in combination. INCAGN02385 will be administered first intravenously followed by INCAGN02390.	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously
Experimental: Phase 1 Part 2; Part 2 will confirm the safety of the triple combination of INCAGN02385 + INCAGN02390 + INCMGA00012, following confirmation of the safety of the doublet in Part 1. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012.	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously; Drug: INCMGA00012.; INCMGA00012 administered intravenously
Experimental: Phase 2 Cohort A; Phase 2 will determine preliminary efficacy and proof of concept for the combination of INCAGN02385 + INCAGN02390 + INCMGA00012. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously; Drug: INCMGA00012.; INCMGA00012 administered intravenously
Experimental: Phase 2 Cohort B; Phase 2 will determine preliminary efficacy and proof of concept for the combination of INCAGN02385 + INCAGN02390 + INCMGA00012. INCAGN02385 will be administered first intravenously followed by INCAGN02390 and INCMGA00012	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously; Drug: INCMGA00012.; INCMGA00012 administered intravenously
Experimental: Phase 1 Part 3; Part 1 will confirm the safety of INCAGN02385 + INCAGN02390 + INCMGA00012 when used in combination.	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously; Drug: INCMGA00012.; INCMGA00012 administered intravenously
Experimental: Phase 1 Part 4; Part 1 will confirm the safety of INCAGN02385 + INCAGN02390 + INCMGA00012 in combination.	Drug: INCAGN02385; INCAGN02385 administered intravenously; Drug: INCAGN02390; INCAGN02390 administered intravenously; Drug: INCMGA00012.; INCMGA00012 administered intravenously

Outcome Measures

Primary Outcome Measures :

1. Phases 1 & 2: Participants with treatment-emergent adverse events (TEAEs) [ Time Frame: 28 days after end of study approximately 24 months ]
   TEAE is defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug
2. Phase 2 Cohort A and B: Objective Response Rate (ORR) [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; approximately 24 months ]
   Defined as the percentage of participants having a Complete Response or Partial Response, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1.
3. Phase 2 Cohort A and B: Duration of Response (DOR) [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; approximately 24 months ]
   Defined as the time from earliest date of disease response (CR or PR) until earliest date of disease progression, as determined by investigator assessment of radiographic disease per RECIST v1.1, or death from any cause, if occurring sooner than progression.
4. Phase 2 Cohort A and B: Disease Control Rate (DCR) [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; approximately 24 months ]
   Defined as percentage of participants having CR, PR, or SD as best on-study response.
5. Phase 2 Cohort A and B: Progression-free Survival (PFS) [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; approximately 24 months ]
   Defined as the time from date of first dose of study treatment until the earliest date of disease progression, as determined by investigator assessment of objective radiographic disease per RECIST v1.1

Secondary Outcome Measures :

1. Phase 1 : Objective Response Rate [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; aprroximately 24 months ]
   Defined as the percentage of participants having a Complete Response or Partial Response, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1.
2. Phase 1 : Progression Free Survival [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; aprroximately 24 months ]
   Defined as the time from date of first dose of study treatment until the earliest date of disease progression, as determined by investigator assessment of objective radiographic disease per RECIST v1.1.
3. Phase 1: Disease Control Rate (DCR) [ Time Frame: Every 8 weeks for first 12 months, and every 12 weeks until disease progression; approximately 24 months ]
   Defined as percentage of participants having CR, PR, or SD as best on-study response

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Phase 1 Parts 1-4): Participants with locally advanced or metastatic solid tumors (locally advanced disease must not be amenable to resection with curative intent) that have failed available therapies, including anti-PD-(L)1 therapy if applicable, that are known to confer clinical benefit, or who are intolerant to, or ineligible for standard treatment. Prior anti-PD-(L)1 therapy should not have been discontinued because of intolerance.

• Phase 2, Cohort A:

  1. Participant with histologically confirmed unresectable/metastatic melanoma, whose disease failed prior anti-PD-(L)1 therapy (alone or as part of a combination) and meeting one of the following criteria:

     • Participant who failed prior adjuvant anti-PD-(L)1 therapy for resectable melanoma must have received prior anti-PD-(L)1 for ≥ 6 weeks and experienced disease progression while still on active adjuvant therapy containing anti-PD-(L)1, or participant who had early relapse occurring < 24 weeks after end of adjuvant anti-PD-(L)1 therapy. Progressive disease must be ascertained by confirmatory biopsy collected at baseline.
     • Participant whose unresectable/metastatic disease progressed while on or within < 24 weeks of completion of anti-PD-(L)1 for inresectable/metastatic melanoma. Progressive disease must have been confirmed by imaging ≥ 4 weeks after evidence of initial disease progression.
  2. Participant must have received no more than 2 prior lines of therapy for melanoma and at least one prior regimen must have contained anti-PD-(L)1 therapy (alone or as part of a combination) either in the adjuvant and/or advanced/metastatic setting.
  3. Participants must have had known BRAF V600 mutation status per local institutional testing standards.
  4. Participants must have fresh biopsy available after completing prior PD-(L)1 therapy or be willing and able to safely undergo pretreatment tumor biopsies (core or excisional). Determination of whether participants can safely undergo biopsy should be made by the treating physician in consultation with the individual performing the biopsy.
  5. Participant must have at least 1 measurable tumor lesion per RECIST v1.1.

• Phase 2, Cohort B:

  1. Participant with previously untreated, histologically confirmed Stage III (unresectable) or IV melanoma per the American Joint Committee on Cancer v8 staging system.
  2. Participants must not have had prior systemic anticancer therapy for unresectable or metastatic melanoma.
  3. Participants must have had known BRAF V600 mutation status per local institutional testing standards.
  4. Participants must have fresh biopsy available or be willing and able to safely undergo pretreatment tumor biopsies (core or excisional). Determination of whether participants can safely undergo biopsy should be made by the treating physician in consultation with the individual performing the biopsy.
• Phase 2 (Cohorts A and B): Participant must have at least 1 measurable tumor lesion per RECIST v1.1.
• ECOG performance status 0 or 1.
• Willingness to avoid pregnancy or fathering children

Exclusion Criteria:

• Laboratory and medical history parameters outside the protocol-defined range.
• Known hypersensitivity or severe reaction to any component of the study drugs or formulation components ) within 14 days before study Day 1.
• Participant who had prior treatment with a LAG-3 or TIM-3 targeted agent.

Phase 1: (Parts 1-4):

• Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study treatment:

  1. ≤28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational agents or devices. For investigational agents with long half-lives (eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval.
  2. Administration of colony-stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 14 days before study Day 1.
• Phase 2:
• Cohort A: Participant who has discontinued anti-PD-(L)1 therapy due to toxicity or other reasons unrelated to toxicity, then subsequently experienced disease progression.
• Cohort A: Participant who had experienced objective response (PR/CR) and had stopped anti-PD-(L)1 therapy due to maximal benefit.
• Cohort A: Participant with multiple metastases that achieved mixed tumor response to prior anti-PD-(L)1 therapy (such as isolated progressive lesion in a context of PR/CR or SD for other lesions) or achieved overall disease progression based only on a single new lesion.
• Cohort B: Participant who has or has had uveal melanoma.
• Receipt of anticancer therapy (immunotherapy, chemotherapy, targeted therapy or hormonal therapy) within 21 days of the first administration of study treatment, with the exception of localized radiotherapy.
• Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months of the first dose of study treatment.
• If participant received major surgery, then they must have recovered adequately from toxicities and/or complications from the intervention before starting study treatment.
• Treatment-related toxicity related to prior therapy that has not recovered to ≤ Grade 1 (with the exception of alopecia and anemia not requiring transfusional support), unless approved by the medical monitor.
• History of immune-related toxicity during prior checkpoint inhibitor therapy for which permanent discontinuation of therapy is recommended (per product label or consensus guidelines), OR any immune-related toxicity requiring intensive or prolonged immunosuppression to manage (with the exception of endocrinopathy that is well controlled on stable dose of replacement hormones such as hypothyroidism or adrenal insufficiency, or Grade 3 rashes that resolved with topical therapy or asymptomatic lipase elevations that do not require treatment interruption or uveitis that resolved with steroid drops).
• Has an active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 14 days before the first dose of study treatment.
• Receiving chronic systemic corticosteroids (> 10 mg/day of prednisone or equivalent).
• Active infections requiring systemic antibiotics, or antifungal or antiviral treatment within 7 days before first dose of study treatment.
• History of organ transplant, including allogeneic stem cell transplantation.
• Evidence of interstitial lung disease or active, noninfectious pneumonitis.
• Known active HBV or HCV infection or risk of reactivation of HBV or HCV.
• Participants who are known to be HIV-positive .
• Known active brain or CNS metastases including carcinomatous meningitis.
• Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy after treatment with curative intent.
• Participants with impaired cardiac function or clinically significant cardiac disease
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.
• Women who are pregnant or breastfeeding.
• Receipt of a live vaccine within 30 days of planned start of study treatment.

Contacts and Locations

Contacts

Contact: Incyte Corporation Call Center (US); 1.855.463.3463; medinfo@incyte.com

Contact: Incyte Corporation Call Center (ex-US); +800 00027423; eumedinfo@incyte.com

Locations

United States, California

The Angeles Clinic and Research Institute; Recruiting

Los Angeles, California, United States, 90025

United States, Florida

H Lee Moffitt Cancer Center and Research; Not yet recruiting

Tampa, Florida, United States, 33612

United States, Iowa

University of Iowa; Recruiting

Iowa City, Iowa, United States, 52242

United States, Maryland

Cancer Center For Blood Disorders; Recruiting

Bethesda, Maryland, United States, 20817

United States, Missouri

Washington University; Not yet recruiting

Saint Louis, Missouri, United States, 63110

United States, New Jersey

John Theurer Cancer Center, Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

United States, New York

Nyu Langone Laura and Isaac Perlmutter Cancer Center; Recruiting

New York, New York, United States, 10016

United States, North Carolina

Carolina Bio Oncology; Recruiting

Huntersville, North Carolina, United States, 28078

United States, Pennsylvania

Penn State Hershey Cancer Institute; Not yet recruiting

Hershey, Pennsylvania, United States, 17033

Hillman Cancer Center; Completed

Pittsburgh, Pennsylvania, United States, 15232

United States, Washington

University of Washington-Seattle Cancer Care Alliance; Recruiting

Seattle, Washington, United States, 98109

Australia, New South Wales

Melanoma Institute Australia; Not yet recruiting

Wollstonecraft, New South Wales, Australia, 02060

Australia, Queensland

Greenslopes Private Hospital; Not yet recruiting

Greenslopes, Queensland, Australia, 04120

Australia, South Australia

Flinders Medical Centre; Not yet recruiting

Bedford Park, South Australia, Australia, 05042

Australia, Victoria

Box Hill Hospital; Not yet recruiting

Box Hill, Victoria, Australia, 03128

Australia, Western Australia

One Clinical Research; Not yet recruiting

Nedlands, Western Australia, Australia, 06009

Sponsors and Collaborators

Incyte Corporation

More Information

• Responsible Party: Incyte Corporation
• ClinicalTrials.gov Identifier: NCT04370704
• Other Study ID Numbers: INCAGN 2385-201
• First Posted: May 1, 2020
• Last Update Posted: June 1, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
• Access Criteria: Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.
• URL: https://www.incyte.com/our-company/compliance-and-transparency

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

Keywords provided by Incyte Corporation:

PD-1 Inhibitors; INCAGN02385; INCAGN02390; INCMGA00012; Retifanlimab

Additional relevant MeSH terms:

Melanoma; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas