| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Selected advanced cancers, including metastatic and/or unresectable solid tumors including NSCLC, melanoma,adenocarcinoma of the colon or rectum , recurrent squamous cell carcinoma of the head and neck, ovarian cancer, recurrent B cell NHL (including DLBCL) or HL, or glioblastoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Selected advanced cancers including lung , melanoma, colon or rectum cancer, head and neck , ovarian , B cell non-Hodgkin's lymphoma or Hodgkin's lymphoma, or glioblastoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 assess the safety and tolerability of epacadostat orally in combination with nivolumab 3 mg/kg every 2 weeks intravenously (IV), and to identify dose-limiting toxicities (DLTs) and the recommended Phase 2 dose (RP2D) of the combination, in subjects with select advanced (metastatic and/or unresectable) cancers (solid tumors and B cell non-Hodgkin's lymphoma [NHL] or Hodgkin's lymphoma [HL]). (Phase 1)
•To assess objective response rate (ORR) and progression-free survival (PFS) at 6 months in subjects with select cancers as measured by modified RECIST v1.1 for select solid tumors or the Revised Response Criteria for Malignant Lymphoma (Cheson criteria) for diffuse large B-cell lymphoma (DLBCL). (Phase 2)
•To assess overall survival at 9 months for subjects with glioblastoma. (Phase 2)
|
|
| E.2.2 | Secondary objectives of the trial |
•To assess the preliminary antitumor activity of the combination of epacadostat and nivolumab in subjects with select advanced solid tumors and B cell NHL or HL including duration of response, PFS, and duration of disease control as measured by modified RECIST v1.1 for solid tumors, modified Cheson criteria for B-cell NHL (including DLBCL) or HL , or modified Response Assessment in Neuro-Oncology (RANO) criteria for subjects with glioblastoma. (Phase 1 and Phase 2)
•To assess the safety and tolerability of epacadostat twice daily (BID) orally in combination with nivolumab 240 mg every 2 weeks. (Phase 2)
•To assess ORR and PFS at 6 months in subjects with advanced (metastatic and/or unresectable) cancers (select solid tumor and B cell NHL or HL). (Phase 1)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Male or female subjects, age 18 years or older.
•Subjects with histologically or cytologically confirmed NSCLC, MEL, CRC, SCCHN, ovarian cancer, recurrent B cell NHL or HL, or glioblastoma.
•Subjects with Stage IIIB, Stage IV, or recurrent NSCLC; unresectable or Stage IV MEL; recurrent (unresectable) or metastatic CRC; recurrent (unresectable) or metastatic SCCHN; FIGO Stage Ic, II, III, or IV recurrent ovarian cancer (unresectable), relapsed or refractory B cell NHL or HL (including relapsed or refractory DLBCL), or glioblastoma and meet the tumor specific criteria
•Presence of measurable disease by RECIST v1.1 for solid tumors or Cheson criteria for B cell NHL (including DLBCL) or HL. For subjects with glioblastoma, presence of measurable disease is not required.
•ECOG performance status 0 to 1.
•Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of the most recent prior chemotherapy regimen) are required for all cohorts except glioblastoma.
•Female subjects of childbearing potential (defined as women who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and are not postmenopausal (defined as ≥12 months of amenorrhea) must have a negative serum pregnancy test at screening. All female (and male as appropriate for Protocol) subjects of childbearing potential must agree to take appropriate precautions to avoid pregnancy (or fathering children), with at least 99% certainty, from screening through 150 days after the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
•Laboratory and medical history parameters not within Protocol-defined range unless directly resulting from the bone marrow infiltration of the underlying malignancy. All screening laboratory tests should be performed within 7 days of treatment initiation and must be independent of hematopoietic growth factor support:
Absolute neutrophil count < 1.5 × 109/L (in no case < 1.0 × 109/L).
Platelets < 100 × 109/L (in no case < 50 × 109/L).
Hemoglobin < 9 g/dL or ≤ 5.6 mmol/L (transfusion is acceptable to meet this criterion).
Serum creatinine > 1.5 × institutional upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of creatinine or CrCl) < 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN.
Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase > 2.5 × ULN.
Total bilirubin above the institutional ULN or conjugated bilirubin ≥ 1.2 × ULN (need only be tested if total bilirubin exceeds ULN). If an institutional ULN for conjugated bilirubin is not available, then conjugated bilirubin should be < 40% of total bilirubin to be considered eligible.
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 (aPTT) > 1.5 × ULN unless subject is receiving anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants.
•Current pregnancy or breastfeeding.
•Participation in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) before first dose.
•Subjects who have received prior immune checkpoint inhibitors (eg, anti–CTLA-4, anti–programmed death receptor 1, anti–PD-L1, and any other antibody or drug specifically targeting T-cell costimulation) or an IDO inhibitor. Anti-CTLA-4 given as first-line treatment for metastatic melanoma will be permitted. These subjects must have discontinued anti-CTLA-4 therapy at least 12 weeks prior to first dose of study treatment.
•Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA-4 treatment, or any unresolved irAE>Grade 1.
•Subjects who are receiving an immunologically based treatment for any reason, including chronic use of systemic steroid or prednisone equivalent at doses ≥ 10 mg/day prednisone equivalent within 7 days prior to the first dose of study treatment. Use of inhaled or topical steroids or systemic corticosteroids < 10 mg is permitted.
•Subjects who have received any anticancer medication in the 21 days prior to receiving their first dose of study medication or has any unresolved toxicity greater than Grade 1 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue.
•Prior monoclonal antibody within 4 weeks before study Day 1 or not recovered (≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
•Untreated central nervous system (CNS) metastases or CNS metastases that have progressed.
•Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, etc.) or who are receiving systemic therapy for an autoimmune or inflammatory disease.
•Evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment.
•Subjects who have had prior radiotherapy within 2 weeks of therapy.
•Known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA [qualitative] is detected).
•Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs.
•History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful.
•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.
•Known allergy or reaction to any component of either study drug formulation.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Safety is the primary endpoint of this Phase 1 study. All subjects who receive at least 1 dose of epacadostat or nivolumab will be assessed for safety by monitoring the frequency and severity of adverse events (AEs), serious adverse events (SAEs), and deaths.
•For Phase 2, the overall objective response rate (ORR) will be assessed based on modified RECIST v1.1 criteria for select solid tumors or modified Cheson criteria for DLBCL and PFS rates at 6 months.
•For Phase 2, overall survival will be assessed at 9 months for subjects with glioblastoma as determined by death due to any cause.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety throughout the trial; PFS rates at 6 months. |
|
| E.5.2 | Secondary end point(s) |
•Efficacy: The duration of response and duration of disease control will be assessed based on modified RECIST v1.1 criteria for select solid tumors, modified Cheson criteria for B cell NHL (including DLBCL) or HL, or modified RANO criteria for subjects with glioblastoma. In addition, PFS rates will be assessed at prespecified timepoints, for example, at 6 months.
•Safety: All subjects who receive at least 1 dose of epacadostat or nivolumab will be assessed for safety by monitoring the frequency and severity of AEs, SAEs, and deaths. (Phase 2)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the trial the duration of response and duration of disease control |
|
| 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 | Yes |
| 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 |
| Investigative combination trial |
|
| 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 | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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
|
| When all subjects have discontinued the study or are a minimum of 6 months after initial study medication administration. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
