| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1 (Dose Escalation): Advanced or metastatic solid tumors.
Phase 2 (Dose Expansion): Advanced or metastatic non–small cell lung cancer (NSCLC), unresectable or metastatic melanoma (MEL) and recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Phase 1 Advanced or metastatic solid tumors. Phase 2 Advanced or metastatic non–small cell lung cancer, unresectable or metastatic melanoma and recurrent or metastatic head and neck 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 | PT |
| E.1.2 | Classification code | 10050017 |
| E.1.2 | Term | Lung cancer metastatic |
| 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 | PT |
| E.1.2 | Classification code | 10027480 |
| E.1.2 | Term | Metastatic malignant melanoma |
| 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 | 10027150 |
| E.1.2 | Term | Melanoma malignant |
| 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 | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| 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 | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck 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 | PT |
| E.1.2 | Classification code | 10071540 |
| E.1.2 | Term | Head and neck cancer metastatic |
| 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 |
To evaluate the safety, tolerability, and DLTs and to define a MTD and/or PAD of epacadostat in combination with nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, in subjects with advanced or metastatic solid tumors.
Group A: To evaluate the efficacy of epacadostat in combination with nivolumab and ipilimumab in subjects with advanced or metastatic NSCLC and unresectable or metastatic MEL by assessing objective response rate (ORR) per RECIST v1.1.
Group B: To evaluate the efficacy of epacadostat in combination with nivolumab and lirilumab in subjects with recurrent or metastatic SCCHN by assessing ORR per RECIST v1.1. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1: To evaluate the efficacy of epacadostat in combination with nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, in subjects with advanced or metastatic solid tumors by assessing ORR per RECIST v1.1.
Phase 1 and 2: To evaluate the efficacy of epacadostat in combination with nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, in subjects with advanced or metastatic solid tumors in Phase 1 and in subjects with selected advanced or metastatic solid tumors in Phase 2 by assessing DOR and PFS per RECIST v1.1.
Phase2: To further evaluate the safety and tolerability of epacadostat at the MTD and/or PAD in combination with nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, in subjects with selected advanced or metastatic solid tumors. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1 only:
• Subjects with histologically or cytologically confirmed locally advanced or metastatic solid tumors who have disease progression on or after treatment with available therapies that are known to confer clinical benefit, or who are intolerant to treatment, or who refuse standard treatment.
Phase 2:
Cohort A1 (MEL):
• Subjects with histologically confirmed unresectable Stage III or Stage IV MEL not amenable to local therapy who have received no prior systemic treatment (excluding adjuvant or neoadjuvant chemotherapy) for advanced or metastatic disease. Mucosal or cutaneous MEL is acceptable; however, subjects with ocular MEL are excluded.
− Must have documentation of BRAF mutation status.
Cohort A2 (NSCLC):
• Subjects with histologically or cytologically confirmed Stage IIIB, Stage IV, or recurrent squamous or nonsquamous NSCLC and who have received no more than 1 prior line of platinum-based chemotherapy for advanced or metastatic disease.
− Subjects with known driver mutations (including EGFR or BRAF mutations, or ALK or ROS1 rearrangements) are excluded.
− Prior adjuvant or neoadjuvant chemotherapy completed less than 6 months before study entry will be counted as 1 prior line of therapy.
Cohort B1 (SCCHN):
• Subjects with histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx that is not amenable to local therapy with curative intent (surgery or radiation with or without chemotherapy) and who have received no more than 1 prior line of platinum-based chemotherapy for recurrentor metastatic disease.
− Must have documentation of human papillomavirus status (eg, p16 status) of tumor (oropharyngeal only).
− Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx and salivary gland or nonsquamous histologies are excluded.
Phase 2 (all cohorts):
• Willingness to undergo serial pretreatment and on-treatment core or excisional tumor biopsies.
All subjects (Phase 1 and 2):
• Ability to comprehend and willingness to sign an informed consent form.
• Men or women aged 18 years or older.
• Presence of measurable disease per RECIST v1.1. Tumor lesions located in a previously irradiated area, or in an area subjected to other locoregional therapy, are considered measurable if progression has been demonstrated in the lesion following such therapy.
• ECOG performance status of 0 or 1.
• Expected survival of ≥ 12 weeks.
• Willingness and ability to comply with the scheduled visits, treatment plan, and laboratory tests.
|
|
| E.4 | Principal exclusion criteria |
• Laboratory and medical history parameters not within the Protocol-defined range; all screening laboratory tests should be performed within 7 days of Cycle 1 Day 1.
− Absolute neutrophil count < 1.5 × 109/L.
− Platelets < 100 × 109/L.
− Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this criterion).
− Serum creatinine ≥ 1.5 × institutional ULN, or measured or calculated creatinine clearance (CrCl) < 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN (glomerular filtration rate can also be used in place of CrCl).
− Phase 1 only: AST or ALT ≥ 1.5 × institutional ULN.
− Phase 2 only: AST or ALT ≥ 2.5 × institutional ULN.
− Total bilirubin ≥ 1.5 × institutional ULN or conjugated (direct) bilirubin ≥ institutional ULN.
− International normalized ratio or prothrombin time > 1.5 × institutional ULN.
− Activated partial thromboplastin time > 1.5 × institutional ULN unless subject is receiving anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants.
− Phase 1 only: Albumin ≤ 3.0 g/dL or with medical monitor approval.
• Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:
− ≤ 21 days for chemotherapy or targeted small-molecule therapy
− ≤ 28 days for previous monoclonal antibody used for anticancer therapy.
− ≤ 28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1 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.
• Previous radiotherapy within 7 days of Cycle 1 Day 1 (except for radiation to CNS, which requires a ≥ 28-day washout). Subjects must also not require chronic use of corticosteroids and must not have had radiation pneumonitis as a result of treatment.
• Known active CNS metastases and/or carcinomatous meningitis.
• Prior treatment with any immune checkpoint inhibitor and/or an IDO inhibitor.
• Any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve
• Subjects who are receiving an immunologically based treatment for any reason, including chronic use of systemic steroid or at doses ≥ 10 mg/day prednisone equivalent within 7 days before the first dose of study drug.
• Receipt of a live vaccine within 30 days of planned start of study therapy.
• Active infection requiring systemic therapy.
• Subjects with any active or inactive autoimmune disease or syndrome that has required systemic treatment in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory disease (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
• Evidence of interstitial lung disease or active, noninfectious pneumonitis, including symptomatic and/or pneumonitis requiring treatment.
• History of organ transplant that requires use of immunosuppressive therapy.
• Has 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 the screening visit.
− Hepatitis C antibody testing is allowed for screening purposes where HCV RNA is not standard of care.
− Subjects who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at the screening visit.
• Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.
• Clinically significant cardiac disease
• Bleeding associated with tumors that invade or are adjacent to major blood vessels, as shown unequivocally by imaging studies, or history of bleeding related to disease under study within 3 months of enrollment.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Women who are pregnant or breastfeeding.
• Excessive alcohol use (> 2 drinks per day).
• Excessive chronic acetaminophen (paracetamol) use (> 2 g per day).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed by monitoring frequency, duration, and severity of AEs through physical examinations, by evaluating changes in vital signs and ECGs, and through clinical laboratory blood and urine sample evaluations.
ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator evaluation of radiographic disease assessment per RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety throughout the trial; eefficacy is assessed every 8 weeks (± 7 days) from the first dose of treatment for the first 12 months and then every 12 weeks (± 7 days) thereafter or more frequently if clinically indicated.
Per RECIST v1.1 and iRECIST, response should be confirmed by a repeat radiographic assessment not less than 4 weeks from the date the response was first documented. |
|
| E.5.2 | Secondary end point(s) |
ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator evaluation of radiographic disease assessment per RECIST v1.1.
DOR is defined as the time from the earliest date of CR or PR until the earliest date at which progression criteria are met as determined by investigator evaluation of radiographic disease assessment per RECIST v1.1, or date of death due to any cause.
PFS is defined as the time from the start of combination therapy until the earliest date at which progression criteria are met as determined by investigator evaluation of radiographic disease assessment per RECIST v1.1, or date of death due to any cause.
Safety and tolerability will be assessed by monitoring frequency, duration, and severity of AEs through physical examinations, by evaluating changes in vital signs and ECGs, and through clinical laboratory blood and urine sample evaluations. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety throughout the trial; eefficacy is assessed every 8 weeks (± 7 days) from the first dose of treatment for the first 12 months and then every 12 weeks (± 7 days) thereafter or more frequently if clinically indicated.
Per RECIST v1.1 and iRECIST, response should be confirmed by a repeat radiographic assessment not less than 4 weeks from the date the response was first documented.
Imaging should continue to be performed until documented iCPD the start of new anticancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. |
|
| 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 |
| safety, tolerability, define a MTD and or PAD of epacadostat in combination |
|
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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