E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ph1: adv. or metast. cervical cancer, endometrial cancer, gastric cancer, hepatocellular carcinoma, melanoma, Merkel cell carcinoma, mesothelioma, MSI-H colorectal cancer, non–small cell lung cancer, ovarian cancer, squamous cell carcinoma of the head and neck (SCCHN), small cell lung cancer, renal cell carcinoma, triple-negative breast cancer, urothelial carcinoma or others.
Ph2: adv. or metast. cervical cancer, gastric cancer, SCCHN, PD-1 refractory SCCHN, and PD-1 or PD-L1 relapsed melanoma |
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E.1.1.1 | Medical condition in easily understood language |
melanoma, mesothelioma, cervical, gastric, liver, skin, colorectal, lung, ovarian, head and neck, kidney, breast and bladder cancer
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041067 |
E.1.2 | Term | Small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060121 |
E.1.2 | Term | Squamous cell carcinoma of head and neck |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014733 |
E.1.2 | Term | Endometrial cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027407 |
E.1.2 | Term | Mesothelioma malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027150 |
E.1.2 | Term | Melanoma malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064025 |
E.1.2 | Term | Merkel cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017758 |
E.1.2 | Term | Gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008229 |
E.1.2 | Term | Cervical cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 11.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10038408 |
E.1.2 | Term | Renal cell carcinomas |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | Colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10033128 |
E.1.2 | Term | Ovarian cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- Phase 1: To evaluate the safety, tolerability, and DLTs of INCAGN01876 in combination with immune therapies and to define the RP2D(s) of INCAGN01876 when given in combination with immune therapies.
- Phase 2: To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies by assessing ORR per RECIST v1.1. |
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E.2.2 | Secondary objectives of the trial |
Phase 1 and Phase 2:
• To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies by assessing ORR, DOR, DCR, duration of disease control, and PFS per RECIST v1.1 and mRECIST v1.1.
• To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies with respect to 1-year and 2-year OS.
• To evaluate the safety and tolerability of INCAGN01876 when given in combination with immune therapies. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Note: Due to space limitation in this window, a restricted set of subject inclusion criteria are presented below. The complete and detailed criteria are listed in the protocol.
• Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent.
• Phase 1: Subjects with advanced or metastatic cervical cancer, endometrial cancer, gastric cancer (including stomach, esophageal, and GEJ), HCC, melanoma (excluding uveal melanoma), Merkel cell carcinoma, mesothelioma, MSI-H CRC, NSCLC, ovarian cancer, SCCHN, SCLC, RCC, TNBC, and urothelial carcinoma (or alternative tumor types with medical monitor approval).
• Phase 1: Subjects who have disease progression after treatment with available therapies that are known to confer clinical benefit, or who are intolerant to treatment, or who refuse standard treatment. There is no limit to the number of prior treatment regimens.
• Phase 2: Subjects with advanced or metastatic cervical cancer, gastric cancer (including stomach, esophageal, and GEJ), SCCHN, PD-1 refractory SCCHN, or PD-1 or PD-L1 relapsed melanoma.
− For subjects with cervical cancer: should have histologically confirmed squamous cell carcinoma of the cervix.
− For subjects with gastric cancer: adenocarcinoma of the stomach, esophagus, or GEJ.
− For subjects with SCCHN: histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Note: Should consent to have tumor evaluated for HPV and Epstein-Barr virus (EBV) status of the tumor (per local institutional testing), or have documentation of HPV and EBV tumor status. Note: Should have received only 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy). Adjuvant regimens given within 6 months of screening would be counted as first-line therapy. Prior chemotherapy regimen should have been a platinum-containing regimen. Note (Stage 2 only): Should have progressive disease per RECIST v1.1 during or within 6 months after treatment with a platinum-containing regimen. The platinum based therapy must be the last therapy the subject received before enrollment.
-For subjects with PD-1 refractory SCCHN: histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx.
Note: Should consent to have tumor evaluated for HPV and EBV status of the tumor(per local institutional testing), or have documentation of HPV and EBV tumor status.
Note: PD-1 refractory SCCHN is defined as meeting all of the following criteria:
i. Progressive disease per RECIST v1.1 as best overall response to treatment with an anti PD-1 containing regimen that is confirmed at least 4 weeks (no less than28 days) later.
ii. Progressive disease should be at least 12 weeks from first dose of anti–PD-1 therapy and confirmed 4 weeks (no less than 28 days) later.
iii. Should have received prior treatment with anti−PD-1 therapy for advanced or metastatic disease.
iv. Should have received at least 2 doses of a prior anti–PD-1 containing regimen.
v. The PD-1 therapy must be the last therapy the subject received before enrollment.
− Tumor biopsy sample collection
i. For subjects in the biopsy cohort: willingness to undergo pretreatment and on treatment tumor biopsies (core or excisional). Must have cervical cancer, endometrial cancer, gastric cancer (including stomach, esophageal and GEJ), SCCHN, PD-1 refractory SCCHN, PD-1 or PD-L1 relapsed melanoma (excluding uveal melanoma). Note: A baseline biopsy obtained for other purposes before signing consent may be used if the subject has not had any intervening systemic therapy from the time of the biopsy to the start of treatment (ie, Cycle 1 Day 1). Note: Subjects with cervical cancer, gastric cancer and SCCHN (excluding subjects with PD-1 refractory SCCHN) should not have received prior treatment with an immune therapy.
ii For subjects in tumor-specific cohorts: willingness to undergo pretreatment tumor biopsy (core or excisional).
Note: A baseline biopsy obtained for other purposes before signing consent may be used if the subject has not had any intervening systemic therapy from the time of the biopsy to the start of study treatment (ie, Cycle 1 Day 1).
Note: De-identified pathology reports should be provided to the sponsor for confirmation of tumor tissue within the biopsy sample prior to enrollment.
- For subjects with PD-1 or PD-L1 relapsed melanoma: mucosal or cutaneous melanoma is acceptable; however, subjects with uveal melanoma are excluded. Subjects should have documented BRAF mutation status or consent to BRAF mutation testing during the screening period. BRAF mutation status determined as part of a panel of genetic tests performed in a gene expression analysis will also satisfy the inclusion criterion for BRAF mutation testing.
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E.4 | Principal exclusion criteria |
• Laboratory and medical history parameters not within the Protocol-defined range.
− Absolute neutrophil count < 1.0 × 10^9/L
− Platelets < 75 × 10^9/L
− Hemoglobin < 9 g/dL or < 5.6 mmol/L
− Serum creatinine > 1.5 × institutional upper limit of normal (ULN), OR measured or calculated creatinine clearance < 50 mL/min for subjects with creatinine levels > 1.5 × ULN.
− Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≥ 2.5 × ULN.
− Total bilirubin ≥ 1.2 × ULN unless conjugated bilirubin ≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN). If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin.
− International normalized ratio, prothrombin time, or activated partial thromboplastin time > 1.5 × ULN.
• Prior treatment with any TNFSF agonist (eg, glucocorticoid-induced tumor necrosis factor receptor [GITR], OX40, 4-1BB/CD137, CD27, etc), for any indication.
• Transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors within 14 days before study Day 1.
• Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug:
− ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Note: Subjects must not have had radiation pneumonitis as a result of treatment. A 1-week washout is permitted for palliative radiation to non–central nervous system (CNS) disease with medical monitor approval. Note: Bisphosphonates and denosumab are permitted concomitant medications.
− ≤ 28 days for prior immune therapy or persistence of active cellular therapy (ie, chimeric antigen receptor T-cell therapy; other cellular therapies must be discussed with medical monitor to determine eligibility).
− ≤ 28 days for a prior monoclonal antibody used for anticancer therapy with the exception of denosumab.
− ≤ 7 days for immune-suppressive–based treatment for any reason. Note: Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is permitted. Note: Must not require chronic use of corticosteroids. The use of physiologic corticosteroid replacement therapy may be approved after consultation with the medical monitor.
− ≤ 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.
• Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior immune therapy) and/or complications from prior surgical intervention before starting therapy Note: Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such as neuropathy and alopecia) are exceptions and may enroll. Note: Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, scleritis, uveitis) will be excluded. Note: Subjects with a history of a Grade 3 or higher immune-related AE from prior immunotherapies are excluded from the dose escalation portion of the study.
• Active autoimmune disease that required systemic treatment in the past (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Subjects who have not required systemic treatment in the past 2 years should discuss their case with medical monitor to determine eligibility. Note: Subjects with hyper/hypothyroidism, vitiligo, controlled asthma, Type I diabetes, Graves' disease, or Hashimoto's disease are eligible to participate. Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) are not considered a form of systemic treatment and are allowed.
• Known active CNS metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided that they are stable (without evidence of progression by imaging for at least 28 days before the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases or CNS edema, and have not required steroids for at least 7 days before the first dose of study drug.
• Evidence of active, noninfectious pneumonitis or history of interstitial lung disease.
• History or presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically meaningful.
• Evidence of hepatitis B virus or hepatitis C virus infection or risk of reactivation.
• Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Phase 1: Safety and tolerability (frequency, duration, and severity)
- Phase 2: ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
• DOR, defined as the time from the earliest date of disease response (CR or PR) until earliest date of disease progression or death due to any cause, if occurring sooner than progression, will be determined by investigator assessment of radiographic disease assessment per RECIST v1.1 and mRECIST v1.1.
• DCR, defined as the percentage of subjects having CR, PR, or stable disease (SD), will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
• Duration of disease control (CR, PR, and SD) as measured from first report of SD or better until disease progression or death from any cause, if occurring sooner than progression, will be determined by investigator assessment of radiographic disease per RECIST v1.1 and mRECIST v1.1.
• PFS, defined as the time from the start of combination therapy until the earliest date of disease progression or death due to any cause, if occurring sooner than progression, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
• OS determined from the start of combination therapy until death due to any cause. Survival analyses will occur at 1-year, 2-years, and at the end of the study.
• Safety and tolerability will be assessed by monitoring frequency, duration, and severity of AEs. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase 1/2 study exploring safety, tolerability and efficacy |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 7 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
United States |
Belgium |
Italy |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |