| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1: Advanced or metastatic solid tumors
Phase 2: Advanced/metastatic microsatellite stable colorectal cancer (MSS-CRC), biliary tract cancer (BTC), gastroesophageal cancer (GC), and endometrial cancer (EC) and recurrent ovarian cancer (OC) |
|
| E.1.1.1 | Medical condition in easily understood language |
Phase 1: Advanced or metastatic solid tumors
Phase 2: Advanced/metastatic microsatellite stable colorectal cancer, biliary tract, gastroesophageal, endometrial and recurrent ovarian cancer |
|
| 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 | 21.0 |
| 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) |
|
| 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 | 10028982 |
| E.1.2 | Term | Neoplasm biliary tract |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056267 |
| E.1.2 | Term | Gastroesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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) |
|
| 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 | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 assess the safety and tolerability and determine the recommended Phase 2 dose (RP2D) of INCB001158 in combination with chemotherapy.
• Phase 2: To evaluate the objective response rate (ORR) of INCB001158 in combination with chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
• Phase 2: To assess the safety, tolerability, and RP2D of INCB001158 in combination with chemotherapy.
• To evaluate the antitumor effect of INCB001158 in combination with chemotherapy.
• To determine the pharmacokinetics (PK) of INCB001158 in subjects treated with INCB001158 in combination with chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Men or women aged 18 years or older.
• Presence of measurable disease per RECIST v1.1. (If subjects have only 1 measurable lesion per RECIST v1.1, this lesion should not have been in the field of prior irradiation unless there is documented progression of the lesion(s)).
• ECOG performance status 0 to 1.
• Baseline archival tumor specimen available or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or 20 unstained slides from biopsy or resection of primary tumor or metastasis that are ≤ 2 years old.
• Willingness to undergo pretreatment and on-treatment tumor biopsies, until at least 5 evaluable paired specimens are collected in each cohort.
• Have resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia).
• Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters within ≤ 7 days before treatment initiation.
- Absolute neutrophil count ≥ 1.5 × 10^9/L.
- Platelets ≥ 100 × 10^9/L.
- Hemoglobin ≥ 9 g/dL.
- Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or creatinine clearance) ≥ 50 mL/min.
Note: Creatinine clearance should be calculated per institutional standard.
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 × ULN.
- If there is no institutional normal range available for the direct bilirubin, the direct bilirubin should be < 40% of the total bilirubin.
- In no case can total bilirubin exceed 3.0 × ULN.
- Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 × ULN.
- International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or INR is within therapeutic range of intended use of anticoagulants.
- Activated partial thromboplastin time (PTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants.
• Albumin > 3.0 g/dL.
• Phase 1 dose escalation only:
- Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that have failed prior standard therapy (disease progression, subject refusal, or intolerance is also allowable).
- Locally advanced disease must not be amenable to resection with curative intent.
• Phase 2 Expansion Cohort A1 only: Subjects with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum.
• Phase 2 Expansion Cohort B1 only: Subjects with histologically or cytologically confirmed nonresectable advanced or metastatic BTC (intra- or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma).
• Phase 2 Expansion Cohort B2 only: Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal, or fallopian tube carcinoma and carcinosarcomas (Sertoli-Leydig or germ cell cancers are excluded) that have progressed within 6 months of prior cytotoxic chemotherapy.
• Phase 2 Expansion Cohort C1 only: Subjects with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the stomach, esophagus, or gastroesophageal junction.
• Phase 2 Expansion Cohort C2 only: Subjects with histologically or cytologically confirmed advanced or metastatic endometrial carcinoma.
• Phase 2 Expansion Cohort C3 only: Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal or fallopian tube carcinoma and carcinosarcomas that have progressed within 6 months of prior cytotoxic chemotherapy (Sertoli-Leydig or germ cell cancers are excluded).
|
|
| E.4 | Principal exclusion criteria |
• Participation in any other study in which receipt of an investigational study drug or device occurred within 28 days or 5 half-lives (whichever is longer) before first dose. For investigational agents with long half-lives (eg, 5 days), enrollment before the fifth half-life requires medical monitor approval.
• Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before administration of study drug.
- Exception: Washout of immune checkpoint inhibitor therapy is NOT required.
- Exception: Denosumab may be used.
• Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before administration of study treatment.
• Has received prior approved radiotherapy within 14 days of study therapy (exception for radiation to central nervous system [CNS], which requires ≥ 28-day washout as described below).
Note: Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiation therapy) to non-CNS disease
• Subjects must not have received therapy with an arginase inhibitor.
Note: Prior immunotherapy treatment with an anti–programmed death-1 receptor, anti–programmed death-1 receptor ligand, anti–programmed death-2 receptor ligand, anti–cytotoxic T-lymphocyte–associated protein 4, anti-CD137, or any other antibody or drug specifically targeting immune checkpoint pathways is allowed.
• Has had major surgery within 4 weeks before enrollment (C1D1).
• Has had 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, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the subject has been disease-free for > 1 year, after treatment with curative intent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone equivalent in dose) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority.
• Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C.
- Hepatitis B virus DNA must be undetectable and HBsAg negative at screening visit.
- Hepatitis C antibody testing is allowed for screening purposes in countries where hepatitis C virus (HCV) RNA is not part of standard-of-care treatment. In these cases, HCV antibody-positive patients will be excluded.
- Subjects who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at screening visit.
• Has 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 cerebral edema, and have not required steroids for at least 14 days before the first dose of study drug.
Note: Subjects with evidence of cerebral edema or those with < 28 days since radiation therapy to the CNS will be excluded from study.
• Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from previous surgical intervention before starting study therapy.
Note: Subjects with stable chronic AEs (≤ Grade 2) not expected to resolve (eg, alopecia) are exceptions and may enroll.
Note: Subjects with a history of peripheral neuropathy ≥ Grade 2 will be excluded.
• Has a known or suspected defect in the function of the urea cycle, including a known deficiency of carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, N-acetyl glutamate synthetase, or arginase.
• Evidence of interstitial lung disease or active, noninfectious pneumonitis.
• Active infection requiring systemic therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Phase 1: Safety, tolerability, dose-limiting toxicities (DLTs), and RP2D of INCB001158 in combination with chemotherapy, as assessed by adverse events (AEs), clinical laboratory tests, physical examination results, and 12-lead electrocardiogram (ECG) results.
• Phase 2: ORR, defined as the percentage of subjects having a complete response (CR) or partial response (PR), as determined by investigator assessment of radiographic disease as per RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Phase 1: continuously
• Phase 2: every 8 weeks |
|
| E.5.2 | Secondary end point(s) |
• Phase 2: Safety, tolerability, and RP2D of INCB001158 in combination with chemotherapy, as assessed by AEs, clinical laboratory tests, physical examination results, and 12-lead ECG results.
• ORR, defined as the percentage of subjects having a CR or PR, as determined by investigator assessment of radiographic disease as per RECIST v1.1 (Phase 1 only).
• Duration of response (DOR), defined as the time from earliest date of CR or PR (as determined by investigator assessment of radiographic disease assessment per RECIST v1.1) until the earliest date of disease progression or death due to any cause, if occurring sooner than disease progression.
• Disease control rate (DCR), defined as the percentage of subjects having CR, PR, or stable disease (SD) for at least 8 weeks, as determined by investigator assessment of radiographic disease as per RECIST v1.1.
• Progression-free survival (PFS), defined as the time from the date of first dose of study drug until the earliest date of disease progression (as determined by investigator assessment of radiographic disease assessment per RECIST v1.1), or death due to any cause, if occurring sooner than progression.
• PK of INCB001158 will be assessed by summarizing Cmin, Cmax, tmax, AUC 0-t, and AUC 0-τ. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Safety and tolerability: continuously
• ORR, DoR, DCR, PFS: every 8 weeks
• PK: For the first 12 Subjects Enrolled in Each Chemotherapy Regimen in Phase 2: Sampling in C1D1 and C2D1 : predose, at 0.5h, 1h, 2h, 4h, 6h and 8-10h; In phase 1 and as of the 13th subject in phase 2: sparse pk sampling in C1D1: predose, at 1h and 4h and in C2D1: predose, at 2h and 6-10h
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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 | Yes |
| 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 to Evaluate the Safety, Tolerability, and Efficacy |
|
| 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 | No |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| United States |
| Belgium |
| United Kingdom |
|
| 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
|
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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