Melanoma
Conditions
Keywords
PD-1 Inhibitors, INCAGN02385, INCAGN02390, INCMGA00012, Retifanlimab
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.
Interventions
DRUGINCAGN02385
INCAGN02385 administered intravenously
DRUGINCAGN02390
INCAGN02390 administered intravenously
DRUGINCMGA00012.
INCMGA00012 administered intravenously
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to 1148 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE either reported for the first time or the worsening of a pre-existing event, after the first dose of study drug until 90 days after the last dose of study drug. |
| Phase 1: Number of Participants With Any ≥Grade 3 TEAE | up to 1148 days | The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal. An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as an AE reported either reported for the first time or the worsening of a pre-existing event, after the first dose of study drug until 90 days after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Objective Response Rate (ORR) | up to 325 days | ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR), as determined by investigator assessment of radiographic disease assessments per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (v1.1). |
| Phase 2: Duration of Response (DOR) | up to 325 days | DOR was defined as the time from the earliest date of disease response (CR or PR) until the earliest date of disease progression, as determined by investigator assessment of radiographic disease per RECIST v1.1, or death from any cause, if it occurred sooner than progression. |
| Phase 2: Disease Control Rate (DCR) | up to 325 days beyond Day 56 | DCR was defined as the percentage of participants with CR, PR, or stable disease (SD) as best on-study response on or after Day 56. |
| Phase 2: Progression-free Survival (PFS) | up to 325 days | PFS was defined as the time from the date of the 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, or death due to any cause. |
| Phase 2: Number of Participants With Any TEAE | up to 415 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE either reported for the first time or the worsening of a pre-existing event, after the first dose of study drug until 90 days after the last dose of study drug. |
| Phase 2: Number of Participants With Any ≥Grade 3 TEAE | up to 415 days | The severity of AEs was assessed using CTCAE version 5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal. An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. |
| Phase 1: ORR | up to 1058 days | ORR was defined as the percentage of participants with a CR or PR, as determined by investigator assessment of radiographic disease assessments per RECIST v1.1. |
| Phase 1: DOR | up to 1058 days | DOR was defined as the time from the earliest date of disease response (CR or PR) until the earliest date of disease progression, as determined by investigator assessment of radiographic disease per RECIST v1.1, or death from any cause, if it occurred sooner than progression. |
| Phase 1: DCR | up to 1058 days beyond Day 56 | DCR was defined as the percentage of participants with CR, PR, or SD as best on study response and or after Day 56. |
| Phase 1: PFS | up to 1058 days | PFS was defined as the time from the date of the 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, or death due to any cause. |
Countries
Australia, United States
Participant flow
Pre-assignment details
This study was conducted at 5 study centers in the United States.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.75 years STANDARD_DEVIATION 14.63 |
| Race/Ethnicity, Customized Asian | 4 Participants |
| Race/Ethnicity, Customized Black/African-American | 0 Participants |
| Race/Ethnicity, Customized Captured as "Hispanic" in Database | 0 Participants |
| Race/Ethnicity, Customized Captured as "Other" in Database | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 11 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants |
| Race/Ethnicity, Customized Unspecified | 2 Participants |
| Race/Ethnicity, Customized White/Caucasian | 49 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 10 | 8 / 11 | 2 / 6 | 1 / 6 | 3 / 6 | 2 / 6 | 4 / 16 | 29 / 61 |
| other Total, other adverse events | 8 / 10 | 11 / 11 | 6 / 6 | 5 / 6 | 6 / 6 | 5 / 6 | 14 / 16 | 55 / 61 |
| serious Total, serious adverse events | 4 / 10 | 2 / 11 | 1 / 6 | 4 / 6 | 3 / 6 | 1 / 6 | 2 / 16 | 17 / 61 |
Outcome results
None listed