| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects With Advanced Solid Tumors and Previously Treated Stage IIIB or Stage IV Non–Small Cell Lung Cancer and Stage IV Microsatellite Stable Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects With Advanced Solid Tumors and Previously Treated Non–Small Cell Lung Cancer and Colorectal 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 | 10010035 |
| E.1.2 | Term | Colorectal 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 | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced 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 | 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 | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| 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 | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| 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 |
• Part 1: To evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD; or the maximum tested dose) of the combination in subjects with advanced or metastatic solid tumors.
• Part 2: To evaluate the efficacy of the combination in subjects with previously treated Stage IIIB or Stage IV non–small cell lung cancer (NSCLC), Stage IV microsatellite stable (MSS) colorectal cancer (CRC), and other select solid tumors by assessing the objective response rate (ORR) per RECIST v1.1 at the MTD or maximum tested dose. |
|
| E.2.2 | Secondary objectives of the trial |
• Part 1: To evaluate the efficacy of the combination in subjects with advanced or metastatic solid tumors by assessing ORR per RECIST v1.1 at the MTD or maximum tested dose.
• Part 2: To evaluate the safety and tolerability of the MTD or maximum tested dose of the combination in subjects with previously treated Stage IIIB or Stage IV NSCLC, Stage IV MSS CRC, and other select solid tumors.
Parts 1 and 2:
•To evaluate changes in T-cell infiltration in the tumor microenvironment with the combination treatment in advanced or metastatic solid tumors and previously treated Stage IIIB or Stage IV NSCLC and Stage IV MSS CRC.
• To evaluate the efficacy of the combination in advanced or metastatic solid tumors and previously treated Stage IIIB or Stage IV NSCLC and Stage IV MSS CRC by assessing PFS.
• To evaluate the efficacy of the combination in subjects with advanced or metastatic solid tumors and previously treated Stage IIIB or Stage IV NSCLC and Stage IV MSS CRC by assessing DOR. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female subjects, age 18 years or older on day of signing consent.
• Willingness to provide written informed consent for the study.
Part 1 Only
• Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that have failed prior standard therapy Note: there is no limit to the number of prior treatment regimens.
Part 2 Only
Note: Subjects must have failed available therapies that are known to confer clinical benefit as indicated below, unless they are ineligible, intolerant, or refused standard treatment.
Subjects with histologically or cytologically confirmed NSCLC:
• Stage IIIB or metastatic (Stage IV) NSCLC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment.
• Prior systemic regimens must include previously approved therapies, including a platinum-containing chemotherapy regimen; a tyrosine kinase inhibitor for tumors with driver mutations; and checkpoint inhibitors where approved.
• Must have disease progression on a prior PD-1–pathway targeted agent (Cohorts A-1, A-3, and A-4). The baseline scan for the purposes of this study may serve as the documentation of progression.
Subjects with recurrent (unresectable) or metastatic CRC:
• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
• Confirmed MSS CRC as per local testing.
• Stage IV MSS CRC (according to American Joint Committee on Cancer 7th edition guidelines) who have had disease progression after available therapies for advanced or metastatic disease that are known to confer clinical benefit, been intolerant to treatment, or refused standard treatment.
• Prior systemic regimens must include previously approved therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–VEGF therapy (if no contraindication); and if negative for KRAS, NRAS, and BRAF mutations and no contraindication, an anti-EGFR therapy; and progressed after the last administration of approved therapy
Subjects with HNSCC:
• Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx.
Note: Carcinomas of the nasopharynx, salivary gland, or nonsquamous cell histology are excluded.
• Must have received prior treatment with a platinum-based therapy. Subjects who relapsed within 6 months of adjuvant therapy, including a platinum-containing regimen, may enroll.
• Must have documented human papilloma virus status.
Subjects with melanoma:
• Histologically or cytologically confirmed melanoma.
• Unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer staging system not amenable to local therapy.
• Documentation of V600-activating BRAF mutation status or consent to BRAF.
• V600 mutation testing during the screening period.
• Must not have ocular melanoma.
Subjects with urothelial carcinoma:
• Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, urinary bladder, or urethra that is transitional cell or mixed transitional/nontransitional (predominantly transitional) cell type.
• Stage IV locally advanced or metastatic urothelial carcinoma (according to American Joint Committee on Cancer 7th edition guidelines) with disease progression during or after PD-1 pathway-targeted therapy.
Both Part 1 and Part 2
• Willingness to undergo a pretreatment and on-treatment tumor biopsy to obtain tumor tissue. On-treatment biopsy is optional in Stage 2 of Part 2. Two on-treatment biopsies are mandatory in the Part 2 Treatment Sequencing Biopsy Expansion Cohorts.
• Life expectancy > 12 weeks.
• ECOG performance status of 0 to 1.
• Presence of measureable disease per RECIST v.1.1 as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measureable if progression has been demonstrated in such lesions. The lesion selected for pre- and/or post-treatment biopsy cannot be the only measurable lesion.
• Willingness to avoid pregnancy or fathering children based on the criteria below:
- Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age.)
- Woman of childbearing potential who has a negative serum pregnancy test at screening (must be performed within 72 hours before the first dose of study drug) and who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 120 days after the last dose of study drug.
- Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 120 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
Laboratory and medical history parameters not within Protocol-defined range.
− Absolute neutrophil count < 1.5 × 109/L.
− Platelet count < 100 × 109/L.
− Hemoglobin < 8 g/dL (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, and alkaline phosphatase ≥ 2.5 × ULN.
− Total bilirubin ≥ 1.2 × ULN are excluded unless direct bilirubin is ≤ ULN.
− International normalized ratio or prothrombin time > 1.5 × ULN.
− Activated partial thromboplastin time > 1.5 × ULN.
• Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:
− < 14 days for chemotherapy, targeted small-molecule therapy, or radiation therapy.
− < 14 days for a prior PD-1 pathway–targeted agent.
− < 28 days for prior monoclonal antibody used for anticancer therapy with the exception of PD-1 pathway–targeted agents.
− < 14 days for an immune-suppressive–based treatment for any reason
− < 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational study drugs or devices.
• Has not recovered from toxic effect(s) of prior therapy to ≤ Grade 1.
• Subjects with prior ocular toxicity from prior immune therapy are excluded.
• Subjects who have not recovered adequately from toxicity and/or complications from surgical intervention before starting therapy.
• Subjects who have 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
• Known active CNS metastases and/or carcinomatous meningitis.
• Has received a live vaccine within 30 days of planned start of study therapy.
• Evidence of interstitial lung disease or active, noninfectious pneumonitis.
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.
• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy.
• Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications.
• Subject has a known history of or is positive for hepatitis B or hepatitis C
• Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
• Active infection requiring systemic therapy.
• Known allergy or reaction to any component of the study drugs or formulation components.
• Women who are pregnant or breastfeeding.
• Known additional malignancy that is progressing
• Prior receipt of an IDO inhibitor.
• Receipt of MAOIs within the 21 days before the first dose of study treatment.
• History of serotonin syndrome after receiving 1 or more serotonergic drugs.
• Prior receipt of any formulation of azacitidine, decitabine, or any other hypomethylating agent.
• Known hypersensitivity to any of the active substances or any of their excipients
• Subjects with bleeding associated with tumors in proximity to major blood vessels are excluded except with medical monitor approval.
Part 1 Only
• History of a prior Grade 3 or 4 irAE |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Part 1: Safety and tolerability will be assessed by monitoring the frequency, duration, and severity of adverse events (AEs); through physical examinations; by evaluating changes in vital signs and electrocardiograms (ECGs); and through clinical laboratory blood and urine sample evaluations.
• Part 2: Objective response rate, defined as the percentage of subjects having a complete response (CR) or partial response (PR), will be determined by investigator assessment of radiographic disease as per RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the trial the duration of response and duration of disease
control |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Part 1: Objective response rate, defined as the percentage of subjects having a CR or PR, will be determined by investigator assessment of radiographic disease as per RECIST v1.1.
• Part 2: Safety and tolerability will be assessed by monitoring the 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.
• Parts 1 and 2: Percentage of responders, where a responder is defined as an increase in the number of tumor-infiltrating lymphocyte (TILs) or the ratio of CD8+ lymphocytes to T regulatory cells [Tregs] infiltrating tumor post-treatment versus pretreatment with pembrolizumab and epacadostat in combination with azacitidine evaluated by immunohistochemistry, will be determined.
• Parts 1 and 2: Progression-free survival, defined as the time from date of first dose of study drug until the earliest date of disease progression, will be determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause, if occurring sooner than progression.
• Parts 1 and 2: Duration of response determined by radiographic disease assessment, defined as the time from earliest date of disease response until the earliest date of disease progression per RECIST v1.1, or death due to any cause, if occurring sooner than progression, will be determined.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | 5 |
| 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 | 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 |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study will occur when all subjects have discontinued the study and the last follow-up visit has been performed. If there have been ≤ 5 subjects on study for more than 6 months, a database lock of the study may occur to allow the analysis of the study data. Any remaining subjects may continue to receive study treatment per protocol. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 0 |
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