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

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

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.

Study Overview

• Status: Terminated
• Conditions: Melanoma; Head and Neck Cancer; Pancreatic Cancer; Urothelial Cancer; NSCLC, Non Small Cell Lung Cancer; RCC, Renal Cell Cancer; DLBCL, Diffused Large B Cell Lymphoma; MSS, Microsatellite Stable Colon Cancer; TNBC, Triple Negative Breast Cancer; mCRPC, Metastatic Castration Resistant Prostate Cancer
• Intervention / Treatment: Drug: NIR178; Drug: PDR001

Detailed Description

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 tiple negative breast cancer (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 400 mg 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.

• Study Type: Interventional
• Enrollment (Actual): 315
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1426ANZ
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Novartis Investigative Site
• Austria
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
• Belgium
  • Liege, Belgium, 4000
    • Novartis Investigative Site
• Czechia
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
• Japan
  • Tokyo
    • Koto ku, Tokyo, Japan, 135 8550
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3075 EA
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • California
    • Santa Monica, California, United States, 90904
      • University of California, Los Angeles
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute .
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center/University of Texas
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • The University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NIR178 + PDR001; Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types.	Drug: NIR178; NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis. NIR178 was administered orally twice daily (BID) as a capsule (Part 1, Part 2 and Japanese safety run-in) and as a film-coated table (Part 3). There were up to 3 dose levels assessed: 80, 160 and 240 mg. Three alternative dosing schedules were evaluated: continuous (Part 1, Part 2, Part 3, Japanese safety run-in), 2 weeks on/2 weeks off (Part 2) and 1 week on/1 week off (Part 2). Each cycle consisted of 28 days.; Other Names: taminadenant; Drug: PDR001; PDR001 is a human monoclonal antibody (MAb) administered on Day 1 of each cycle. PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: NIR178 BID Intermittent + PDR001; Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001	Drug: NIR178; NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis. NIR178 was administered orally twice daily (BID) as a capsule (Part 1, Part 2 and Japanese safety run-in) and as a film-coated table (Part 3). There were up to 3 dose levels assessed: 80, 160 and 240 mg. Three alternative dosing schedules were evaluated: continuous (Part 1, Part 2, Part 3, Japanese safety run-in), 2 weeks on/2 weeks off (Part 2) and 1 week on/1 week off (Part 2). Each cycle consisted of 28 days.; Other Names: taminadenant; Drug: PDR001; PDR001 is a human monoclonal antibody (MAb) administered on Day 1 of each cycle. PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: Part 3; 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; NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis. NIR178 was administered orally twice daily (BID) as a capsule (Part 1, Part 2 and Japanese safety run-in) and as a film-coated table (Part 3). There were up to 3 dose levels assessed: 80, 160 and 240 mg. Three alternative dosing schedules were evaluated: continuous (Part 1, Part 2, Part 3, Japanese safety run-in), 2 weeks on/2 weeks off (Part 2) and 1 week on/1 week off (Part 2). Each cycle consisted of 28 days.; Other Names: taminadenant; Drug: PDR001; PDR001 is a human monoclonal antibody (MAb) administered on Day 1 of each cycle. PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes every 4 weeks (Q4W).; Other Names: spartalizumab
Experimental: Japanese safety run-in part; Different dosing schedules of NIR178 were explored.	Drug: NIR178; NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis. NIR178 was administered orally twice daily (BID) as a capsule (Part 1, Part 2 and Japanese safety run-in) and as a film-coated table (Part 3). There were up to 3 dose levels assessed: 80, 160 and 240 mg. Three alternative dosing schedules were evaluated: continuous (Part 1, Part 2, Part 3, Japanese safety run-in), 2 weeks on/2 weeks off (Part 2) and 1 week on/1 week off (Part 2). Each cycle consisted of 28 days.; Other Names: taminadenant; Drug: PDR001; PDR001 is a human monoclonal antibody (MAb) administered on Day 1 of each cycle. PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes every 4 weeks (Q4W).; Other Names: spartalizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Overall Response Rate (ORR) Per 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), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to 3.9 years
Part 1: Overall Response Rate (ORR) Per Cheson 2014 for DLBCL	ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Cheson 2014 criteria for diffuse large B-cell lymphoma (DLBCL). For Cheson 2014 criteria, CR= Target nodes/nodal masses must regress to ≤1.5 cm in longest diameter (LDi), no extralymphatic sites of disease, absent non-measured lesions, organ enlargement regress to normal, no new lesions, and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative); PR= ≥50% decrease in the sum of the product of the perpendicular diameters (SPD) of up to 6 target measurable nodes, absent or regressed non-measured lesions, spleen must have regressed by >50% in length beyond normal, and no new lesions.	Up to 2.5 years
Part 2: Overall Response Rate (ORR) Per 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), based on local investigator assessment per RECIST v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to 4.7 years
Part 3: Overall Response Rate (ORR) Per 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), based on local investigator assessment per RECIST v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to 0.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 3.9 years
Part 2: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 4.7 years
Part 3: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 0.5 years
Part 1: Mean Percentage Change in PSA From Baseline	Prostate-specific antigen (PSA) levels were assessed in serum. Rising PSA is generally a manifestation of progression of prostate cancer.	Baseline, up to 0.8 years
Part 1: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR), stable disease (SD) or Non-CR or Non-progressive disease (NCRNPD), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.	Up to 3.9 years
Part 1: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (iCR), partial response (iPR), stable disease (iSD) or Non-iCR or Non-unconfirmed progressive disease (NON-iCR or NON-iUPD), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 3.9 years
Part 1: Disease Control Rate (DCR) Per Cheson 2014 for DLBCL	DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per Cheson 2014 criteria for diffuse large B-cell lymphoma (DLBCL).	Up to 2.5 years
Part 2: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR), stable disease (SD) or Non-CR or Non-progressive disease (NCRNPD), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.	Up to 4.7 years
Part 2: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (iCR), partial response (iPR), stable disease (iSD) or Non-iCR or Non-unconfirmed progressive disease (NON-iCR or NON-iUPD), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 4.7 years
Part 3: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR), stable disease (SD) or Non-CR or Non-progressive disease (NCRNPD), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.	Up to 0.5 years
Part 3: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	DCR is the percentage of patients with a best overall response of complete response (iCR), partial response (iPR), stable disease (iSD) or Non-iCR or Non-unconfirmed progressive disease (NON-iCR or NON-iUPD), based on local investigator assessment per immune-related RECIST (iRECIST).	Up to 0.5 years
Part 1: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 3.9 years
Part 1: Duration Of Response (DOR) Per iRECIST for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (iCR) or partial response (iPR) based on local investigator assessment per iRECIST. DOR is defined as the time from the date of first documented response (iCR or iPR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 3.9 years
Part 1: Duration Of Response (DOR) Per Cheson 2014 for DLBCL	DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per Cheson 2014 criteria for DLBCL. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 2.5 years
Part 2: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 4.7 years
Part 2: Duration Of Response (DOR) Per iRECIST for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (iCR) or partial response (iPR) based on local investigator assessment per iRECIST. DOR is defined as the time from the date of first documented response (iCR or iPR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 4.7 years
Part 3: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 0.5 years
Part 3: Duration Of Response (DOR) Per iRECIST for Solid Tumors	DOR only applies to patients for whom best overall response is complete response (iCR) or partial response (iPR) based on local investigator assessment per iRECIST. DOR is defined as the time from the date of first documented response (iCR or iPR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 0.5 years
Part 1: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 3.9 years
Part 1: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per iRECIST. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 3.9 years
Part 1: Progression-Free Survival (PFS) Per Cheson 2014 for DLBCL	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per Cheson 2014 for DLBCL. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 2.5 years
Part 2: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 4.7 years
Part 2: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per iRECIST. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 4.7 years
Part 3: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per RECIST v1.1. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 0.5 years
Part 3: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per iRECIST. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan.	Up to 0.5 years
Part 1: 2-year Overall Survival (OS)	OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan (SAP).	2 years
Part 2: 2-year Overall Survival (OS)	OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan.	2 years
Part 3: 2-year Overall Survival (OS)	OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan.	2 years
Part 1: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	The tumor expression of CD8 was measured by immunohistochemical (IHC) methods. Newly obtained pre- and on-treatment paired tumor samples were required and collected at screening and after approximately two cycles of therapy.	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
Part 2: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	The tumor expression of CD8 was measured by immunohistochemical (IHC) methods. Newly obtained pre- and on-treatment paired tumor samples were required and collected at screening and after approximately two cycles of therapy.	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
Part 3: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	The tumor expression of CD8 was measured by immunohistochemical (IHC) methods. Newly obtained pre- and on-treatment paired tumor samples were required and collected at screening and after approximately two cycles of therapy.	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
Part 1, 2 and 3: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.	Up to 4 years (Part 1), 4.8 years (Part 2) and 0.6 years (Part 3)
Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of NIR178	Number of participants with at least one dose reduction of NIR178 and number of participants with at least one dose interruption of NIR178. Dose or schedule adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule.	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of PDR001	Number of participants with at least one dose reduction of PDR001 and number of participants with at least one dose interruption of PDR001. Dose or schedule adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. Dose reductions were not permitted for PDR001.	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
Part 1, 2 and 3: Dose Intensity of NIR178	Dose intensity of NIR178 was calculated as cumulative actual dose in milligrams divided by duration of exposure in days.	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
Part 1, 2 and 3: Dose Intensity of PDR001	Dose intensity of PDR001 was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
Part 1, 2 and 3: Number of Participants With Anti-PDR001 Antibodies	PDR001 immunogenicity was evaluated in serum samples. Patient anti-drug antibodies (ADA) status was defined as follows: ADA-negative at baseline: ADA-negative sample at baseline; ADA-positive at baseline: ADA-positive sample at baseline; ADA-negative post-baseline: ADA-negative sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples; Treatment-reduced ADA-positive: ADA-positive sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples; Treatment-induced ADA-positive: ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample; Treatment-boosted ADA-positive: ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample; ADA-inconclusive: patient who does not qualify for any of the above definitions or a patient for which the baseline sample is missing	Up to approximately 5 years
Japan Safety Run-in: Number of Participants With Dose-Limiting Toxicities (DLTs)	A dose-limiting toxicity (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, which occurs within the first 28 days of treatment with NIR178 as single agent or in combination with PDR001 during the Japan safety run-in part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.	28 days
Japan Safety Run-in: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.	Up to 0.7 years
All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NIR178	Pharmacokinetic (PK) parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NIR178	Pharmacokinetic (PK) parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NIR178	PK parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NJI765 (NIR178 Metabolite)	NJI765 is a NIR178 metabolite. PK parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NJI765 (NIR178 Metabolite)	NJI765 is a NIR178 metabolite. Pharmacokinetic (PK) parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NJI765 (NIR178 Metabolite)	NJI765 is a NIR178 metabolite. PK parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.	Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days
All Study Parts: Maximum Observed Serum Concentration (Cmax) of PDR001	PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.	First dose (Cycle 1 Day 1 or Cycle 2 Day 1 for Japanese patients treated with NIR178 80 or 160 mg) and Cycle 3 Day 1: pre-infusion, 1, 168, 336, 504 and 672 hours after end of infusion. Average duration of infusion=30 minutes. 1 cycle=28 days
All Study Parts: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.	First dose (Cycle 1 Day 1 or Cycle 2 Day 1 for Japanese patients treated with NIR178 80 or 160 mg) and Cycle 3 Day 1: pre-infusion, 1, 168, 336, 504 and 672 hours after end of infusion. Average duration of infusion=30 minutes. 1 cycle=28 days
All Study Parts: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001	PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-28day calculation.	First dose (Cycle 1 Day 1 or Cycle 2 Day 1 for Japanese patients treated with NIR178 80 or 160 mg) and Cycle 3 Day 1: pre-infusion, 1, 168, 336, 504 and 672 hours after end of infusion. Average duration of infusion=30 minutes. 1 cycle=28 days

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2017
• Primary Completion (Actual): February 13, 2023
• Study Completion (Actual): February 14, 2023

Study Registration Dates

• First Submitted: June 19, 2017
• First Submitted That Met QC Criteria: June 30, 2017
• First Posted (Actual): July 5, 2017

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: NSCLC; Immunotherapy; solid tumors; PDR001; NIR178; A2aR
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Kidney Neoplasms; Breast Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Lymphoma; Carcinoma, Renal Cell; Lymphoma, Non-Hodgkin; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Spartalizumab
• Other Study ID Numbers: CNIR178X2201; 2017-000241-49 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No