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

Phase 2

Terminated

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

• Registration Number: NCT03207867
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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 Timeline

• Study First Submitted: 2017-06-19
• Study First Submitted QC: 2017-06-30
• Study First Posted: 2017-07-05
• Study Start: 2017-08-28
• Primary Completion: 2023-02-13
• Study Completion: 2023-02-14
• Results First Submitted: 2024-02-05
• Results First Submitted QC: 2024-02-05
• Results First Posted: 2024-03-01
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-07
• Last Update Posted: 2024-10-09

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 315

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NIR178 + PDR001	PDR001	Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types.
Part 3	PDR001	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.
Japanese safety run-in part	PDR001	Different dosing schedules of NIR178 were explored.
Japanese safety run-in part	NIR178	Different dosing schedules of NIR178 were explored.
NIR178 BID Intermittent + PDR001	NIR178	Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001
Part 3	NIR178	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.
NIR178 + PDR001	NIR178	Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types.
NIR178 BID Intermittent + PDR001	PDR001	Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001

Primary Outcome Measures

Name	Time	Method
Part 3: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors	Up to 0.5 years	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.
Part 1: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors	Up to 3.9 years	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.
Part 1: Overall Response Rate (ORR) Per Cheson 2014 for DLBCL	Up to 2.5 years	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.
Part 2: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors	Up to 4.7 years	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.

Secondary Outcome Measures

Name	Time	Method
Part 1: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	Up to 3.9 years	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).
Part 2: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	Up to 4.7 years	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).
Part 1: Mean Percentage Change in PSA From Baseline	Baseline, up to 0.8 years	Prostate-specific antigen (PSA) levels were assessed in serum. Rising PSA is generally a manifestation of progression of prostate cancer.
Part 1: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	Up to 3.9 years	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).
Part 2: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	Up to 4.7 years	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).
Part 1: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	Up to 3.9 years	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.
Part 1: Duration Of Response (DOR) Per iRECIST for Solid Tumors	Up to 3.9 years	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.
Part 1: Duration Of Response (DOR) Per Cheson 2014 for DLBCL	Up to 2.5 years	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.
Part 3: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	Up to 0.5 years	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.
Part 3: Disease Control Rate (DCR) Per iRECIST for Solid Tumors	Up to 0.5 years	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).
Part 3: Duration Of Response (DOR) Per iRECIST for Solid Tumors	Up to 0.5 years	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.
Part 3: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	Up to 0.5 years	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.
Part 1: 2-year Overall Survival (OS)	2 years	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).
Part 1: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.	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.
Part 3: Overall Response Rate (ORR) Per iRECIST for Solid Tumors	Up to 0.5 years	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).
Part 1: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	Up to 3.9 years	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.
Part 1: Disease Control Rate (DCR) Per Cheson 2014 for DLBCL	Up to 2.5 years	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).
Part 2: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors	Up to 4.7 years	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.
Part 2: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	Up to 4.7 years	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.
Part 2: Duration Of Response (DOR) Per iRECIST for Solid Tumors	Up to 4.7 years	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.
Part 3: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors	Up to 0.5 years	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.
Part 1: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	Up to 3.9 years	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.
Part 1: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	Up to 3.9 years	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.
Part 1: Progression-Free Survival (PFS) Per Cheson 2014 for DLBCL	Up to 2.5 years	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.
Part 2: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	Up to 4.7 years	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.
Part 2: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors	Up to 4.7 years	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.
Part 3: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors	Up to 0.5 years	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.
Part 2: 2-year Overall Survival (OS)	2 years	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.
Part 3: 2-year Overall Survival (OS)	2 years	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.
Part 2: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.	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.
Part 3: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue	Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.	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.
Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of NIR178	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)	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.
Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of PDR001	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)	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.
Part 1, 2 and 3: Dose Intensity of PDR001	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)	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.
All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NJI765 (NIR178 Metabolite)	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	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.
Part 1, 2 and 3: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Up to 4 years (Part 1), 4.8 years (Part 2) and 0.6 years (Part 3)	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.
Part 1, 2 and 3: Dose Intensity of NIR178	Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)	Dose intensity of NIR178 was calculated as cumulative actual dose in milligrams divided by duration of exposure in days.
Part 1, 2 and 3: Number of Participants With Anti-PDR001 Antibodies	Up to approximately 5 years	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
Japan Safety Run-in: Number of Participants With Dose-Limiting Toxicities (DLTs)	28 days	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.
Japan Safety Run-in: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	Up to 0.7 years	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.
All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NIR178	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	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.
All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NIR178	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	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.
All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NIR178	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	PK parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.
All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NJI765 (NIR178 Metabolite)	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	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.
All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NJI765 (NIR178 Metabolite)	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	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.
All Study Parts: Maximum Observed Serum Concentration (Cmax) of PDR001	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	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.
All Study Parts: Time to Reach Maximum Serum Concentration (Tmax) of PDR001	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	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.
All Study Parts: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001	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	PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-28day calculation.

Trial Locations

Locations (6)

H Lee Moffitt Cancer Center and Research Institute .; 🇺🇸 Tampa, Florida, United States

University of California, Los Angeles; 🇺🇸 Santa Monica, California, United States

Novartis Investigative Site; 🇨🇳 Taipei, Taiwan

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

MD Anderson Cancer Center/University of Texas; 🇺🇸 Houston, Texas, United States

The University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States