A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

Detailed Description
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This is an open-label multi-part, phase II study evaluating the combination of NIR178 and PDR001 in patients with advanced solid tumors and diffuse large B cell lymphoma (DLBCL). The study has three parts: Part 1: Multi-arm Bayesian adaptive signal finding design in solid tumors and diffuse large B cell lymphoma (DLBCL) with continuous dosing of NIR178 in combination with PDR001. Part 2: Exploration of continuous and intermittent NIR178 schedules in combination with PDR001 in patients with advanced non-small cell lung cancer (NSCLC). Part 3: Further evaluation of optimal intermittent or continuous schedule of NIR178 in combination with PDR001 (if selected based on results of Part 2). As of protocol amendment 6, Part 3 explored the safety and pharmacokinetics of the film-coated tablet (FCT) formulation of NIR178 continuous dosing in combination with PDR001 in TNBC patients. In addition, a separate safety run-in part was conducted in Japan in order to adequately characterize the safety and pharmacokinetic profiles of NIR178 as a single-agent and in combination with PDR001. Patients enrolled in this study received NIR178 either twice daily (BID) continuously or based on the assigned intermittent schedule within 60 minutes prior to PDR001 infusion. PDR001 was administered via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle was 28 days. Patients enrolled in the Japanese safety run-in part received NIR178 as single agent for the first cycle (28 days). If the patients completed cycle 1 without experiencing dose limiting toxicities (DLTs), they initiated combination therapy with PDR001 starting Cycle 2 onwards, and continued at the same dose of NIR178. An additional cohort in the Japanese safety run-in part of the study received NIR178 in combination with PDR001 starting with Cycle 1. If the patients complete Cycle 1 without experiencing DLTs, they continued to receive combination treatment. Patients received treatment with the combination until disease progression (assessed by investigator per immune-related response criteria (iRECIST) or Cheson 2014), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment.

Official Title
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A Phase 2, Multi-center, Open Label Study of NIR178 in Combination With PDR001 in Patients With Selected Advanced Solid Tumors and Non-Hodgkin Lymphoma

Conditions
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DLBCL, Diffused Large B Cell Lymphoma, NSCLC, Non Small Cell Lung Cancer, RCC, Renal Cell Cancer, Pancreatic Cancer, Urothelial Cancer, Head and Neck Cancer, MSS, Microsatellite Stable Colon Cancer, TNBC, Triple Negative Breast Cancer, Melanoma, mCRPC, Metastatic Castration Resistant Prostate Cancer

Intervention / Treatment
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* Drug: NIR178
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥18 years of age. For Japan only: written consent is necessary both from the patient and his/her legal representative if he/she is under the age of 20 years. Histologically documented advanced or metastatic solid tumors or lymphomas Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic cancer, urothelial cancer, head and neck cancer, diffuse large B-cell lymphoma (DLBCL), microsatellite stable (MSS) colon cancer, triple negative breast cancer (TNBC), melanoma, metastatic castration resistant prostate cancer (mCRPC) Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. For those with mixed histology, there must be a predominant histology Part 3: histologically confirmed diagnosis of selected advanced/metastatic malignancies. Part 3 will be opened to further assess TNBC patients with a PD-L1 SP-142 IC score of 0 (<1%). A second tumor group will be considered for Part 3 after completion of Part 1. Patient (except for those participating in Japanese safety run-in) must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and again during therapy on this study. Safety run-in part in Japanese patients can enroll any tumor type included in part 1, 2 and 3. The collection of recent sample is permitted under the following conditions (both must be met): Biopsy was collected ≤ 6 months before 1st dose of study treatment and available at the site. No immunotherapy was given to the patient since collection of biopsy. - Part 1 - 3 only: Patients (other than those with DLBCL) must previously have received at least 1 and no more than 3 prior lines of therapy for their disease (with the exception of IO-pretreated cutaneous melanoma, HNSCC and RCC), unless considered inappropriate for the patient (e.g. safety concern, label contraindication): Patients with NSCLC must have received a prior platinum-based combination. Patients with EGFR positive NSCLC with a T790M mutation must have progressed on osimertinib or discontinued due to toxicity. Patients with head and neck cancer must have received a prior platinum-containing regimen. Patients with bladder cancer must have received a prior platinum-containing regimen or be ineligible for cisplatin. Patients with renal cell carcinoma must have received a prior VEGF tyrosine kinase inhibitor (TKI). Patients with MSS colorectal cancer must have received (or be intolerant to) prior therapy with fluoropyrimidine-oxaliplatin- and irinotecan- based regimens. Patients with triple negative breast cancer:. Part 1: must have received a prior taxane-containing regimen Part 3: should have received no more than 2 prior lines of therapy including taxane-based chemotherapy and should have a known PD-L1 status as per local available testing as determined by VENTANA PD-L1 SP142 Assay with IC score of 0 (<1%) Patients with DLBCL should be limited to those with no available therapies of proven clinical benefit Patients should have had prior autologous hematopoietic stem cell transplantation (auto-HSCT) or determined to be ineligible for auto-HSCT. Patients with melanoma: BRAF V600E wild type patients: must have received anti-PD-1/PD-L1 single agent, or in combination with anti-CTLA-4 therapy BRAF V600E mutant patients: must have received prior anti-PD-1/PD-L1 single-agent, or in combination with anti-CTLA-4 therapy. In addition, subjects must have received prior BRAF V600E inhibitor therapy, either single-agent or in combination with a MEK inhibitor Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC): Of the 1-3 prior lines of therapy, patients must have received and failed at least one line of treatment after emergence of castration resistant disease Patients must not have received prior immunotherapy (previous immune checkpoint inhibitors; single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1), except for NSCLC patients enrolled in part 3 and Japanese safety run-in part. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral computer tomography (CT) scan, Magnetic Resonance Imaging (MRI), or calipers by clinical exam. Exclusion Criteria: Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with A2aR inhibitors for non-oncologic indications (e.g. Parkinson's disease) may be considered for enrollment on a case by case basis. Current or prior use of immunosuppressive medication within 28 days before the first dose of PDR001, with the exception of intranasal/inhaled corticosteroids or systemic corticosteroids at physiological doses (not exceeding equivalent of 10 mg/day of prednisone) History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease Active or prior documented autoimmune disease within the past 2 years. Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. More than 3 prior lines of therapy except for Japanese safety run-in part. History of interstitial lung disease or non-infectious pneumonitis Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 6 weeks is indicated as washout period. For patients receiving anticancer immunotherapies, 4 weeks is indicated as the washout period. GnRH therapy to maintain effective testosterone suppression levels is allowed for mCRPC patients. Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIR178 + PDR001<br>Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types. | Drug: NIR178<br>* NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.<br>Drug: PDR001<br>* PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle<br>|
| Experimental: NIR178 BID Intermittent + PDR001<br>Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001 | Drug: NIR178<br>* NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.<br>Drug: PDR001<br>* PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle<br>|
| Experimental: Part 3<br>Further evaluation of optimal intermittent or continuous schedule of NIR178 in combination with PDR001 (if selected based on results of Part 2). A film-coated tablet of NIR178 was assessed. | Drug: NIR178<br>* NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.<br>Drug: PDR001<br>* PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle<br>|
| Experimental: Japanese safety run-in part<br>Different dosing schedules of NIR178 were explored. | Drug: NIR178<br>* NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.<br>Drug: PDR001<br>* PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Overall Response Rate (ORR) | Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors) or Cheson (for DLBCL) or PCWG3 criteria for mCRPC. ORR is the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR). | Up to approximately 4 years | 
| Part 2: Overall Response Rate (ORR) | Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors). ORR is the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR). | Up to approximately 5 years | 
| Part 3: Overall Response Rate (ORR) | Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors) or Cheson (for DLBCL) or PCWG3 criteria for mCRPC. ORR is the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR). | Up to approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by iRECIST | ORR by iRECIST is the percentage of patients with a best overall response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR). | Up to approximately 5 years | 
| Best Prostate-specific antigen (PSA) change from baseline (only for mCRPC) | Levels of PSA quantified in blood samples | Baseline, up to approximately 1 year | 
| Disease Control Rate (DCR) | Assessment of efficacy by RECIST v1.1 and iRECIST (for solid tumors), Cheson (for DLBCL), and PCWG3 criteria for mCRPC. DCR is the percentage of patients with a best overall response of CR or PR or Stable Disease (SD) | Up to approximately 5 years | 
| Duration of response (DoR) | Assessment of efficacy by RECIST v1.1 and iRECIST (for solid tumors), Cheson (for DLBCL), and PCWG3 criteria for mCRPC. DOR is the time from first documented response to disease progression. | Up to approximately 5 years | 
| Progression Free Survival (PFS) | Assessment of efficacy by RECIST v1.1 and iRECIST (for solid tumors), Cheson (for DLBCL), and PCWG3 criteria for mCRPC. PFS is the time from start of treatment to date of the first documented progression or death. | Up to approximately 5 years | 
| 2 year Overall Survival (OS) rate | Kaplan-Meier estimates for OS at 24 months | 2 years | 
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs. | Up to approximately 5 years | 
| Number of participants with dose interruptions and reductions of study treatments | Frequency of dose interruptions and reductions | Up to approximately 5 years | 
| Dose intensity of study treatments | Dose intensity is calculated as actual cumulative dose divided by duration of exposure | Up to approximately 5 years | 
| Change from baseline in Tumor infiltrating lymphocytes (TILs) | Quantification of TILs (such as CD8) in tumor samples by immunohistochemistry (IHC) | Baseline, up to approximately 3 months | 
| Peak concentration (Cmax) of NIR178, its metabolite NJI765 and PDR001 | Non-compartmental pharmacokinetic (PK) analysis of plasma concentration-time profiles of NIR178 and NJI765 and serum concentration-time profiles of PDR001. | From pre-dose up to Cycle 6. The duration of one cycle is 28 days. | 
| Time to peak concentration (Tmax) of NIR178, its metabolite NJI765 and PDR001 | Non-compartmental pharmacokinetic (PK) analysis of plasma concentration-time profiles of NIR178 and NJI765 and serum concentration-time profiles of PDR001. | From pre-dose up to Cycle 6. The duration of one cycle is 28 days. | 
| Area under the curve (AUC) of NIR178, its metabolite NJI765 and PDR001 | Non-compartmental pharmacokinetic (PK) analysis of plasma concentration-time profiles of NIR178 and NJI765 and serum concentration-time profiles of PDR001. | From pre-dose up to Cycle 6. The duration of one cycle is 28 days. | 
| Number of participants with anti-PDR antibodies | Anti-PDR001 antibodies determined from serum using validated homogenous Enzyme-Linked Immunosorbent Assay (ELISA). | Up to approximately 5 years | 
| Incidence of Dose-Limiting Toxicities (DLTs) (Japanese Safety run-in only) | A DLT is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first cycle of treatment. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDR001, NIR178, NSCLC, solid tumors, Immunotherapy, A2aR