Clinical trial NCT03207867: A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: NSCLC, Non Small Cell Lung Cancer
RCC, Renal Cell Cancer
Pancreatic Cancer
Urothelial Cancer
Head and Neck Cancer
DLBCL, Diffused Large B Cell Lymphoma
MSS, Microsatellite Stable Colon Cancer
TNBC, Triple Negative Breast Cancer
Melanoma
mCRPC, Metastatic Castration Resistant Prostate Cancer
Keywords: Immunotherapy
A2aR
PDR001
NIR178
NSCLC
solid tumors
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-07-05
Enrollment: 315
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Part 1, Part 3 and the Japanese safety run-in part were not randomized. In Part 2, patients were randomized to one of the 3 treatment arms in a ratio of 1:1:1.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Overall Response Rate (ORR) Per Cheson 2014 for DLBCL
timeFrame: Up to 2.5 years
measure: Part 2: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 3: Overall Response Rate (ORR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 0.5 years
Secondary outcomes:
measure: Part 1: Overall Response Rate (ORR) Per iRECIST for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 2: Overall Response Rate (ORR) Per iRECIST for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 3: Overall Response Rate (ORR) Per iRECIST for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 1: Mean Percentage Change in PSA From Baseline
timeFrame: Baseline, up to 0.8 years
measure: Part 1: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Disease Control Rate (DCR) Per iRECIST for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Disease Control Rate (DCR) Per Cheson 2014 for DLBCL
timeFrame: Up to 2.5 years
measure: Part 2: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 2: Disease Control Rate (DCR) Per iRECIST for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 3: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 3: Disease Control Rate (DCR) Per iRECIST for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 1: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Duration Of Response (DOR) Per iRECIST for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Duration Of Response (DOR) Per Cheson 2014 for DLBCL
timeFrame: Up to 2.5 years
measure: Part 2: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 2: Duration Of Response (DOR) Per iRECIST for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 3: Duration Of Response (DOR) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 3: Duration Of Response (DOR) Per iRECIST for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 1: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors
timeFrame: Up to 3.9 years
measure: Part 1: Progression-Free Survival (PFS) Per Cheson 2014 for DLBCL
timeFrame: Up to 2.5 years
measure: Part 2: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 2: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors
timeFrame: Up to 4.7 years
measure: Part 3: Progression-Free Survival (PFS) Per RECIST v1.1 for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 3: Progression-Free Survival (PFS) Per iRECIST for Solid Tumors
timeFrame: Up to 0.5 years
measure: Part 1: 2-year Overall Survival (OS)
timeFrame: 2 years
measure: Part 2: 2-year Overall Survival (OS)
timeFrame: 2 years
measure: Part 3: 2-year Overall Survival (OS)
timeFrame: 2 years
measure: Part 1: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue
timeFrame: Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
measure: Part 2: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue
timeFrame: Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
measure: Part 3: Change From Baseline in CD8 Percent Marker Area in Tumor Tissue
timeFrame: Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.
measure: Part 1, 2 and 3: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: Up to 4 years (Part 1), 4.8 years (Part 2) and 0.6 years (Part 3)
measure: Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of NIR178
timeFrame: Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
measure: Part 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of PDR001
timeFrame: Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
measure: Part 1, 2 and 3: Dose Intensity of NIR178
timeFrame: Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
measure: Part 1, 2 and 3: Dose Intensity of PDR001
timeFrame: Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)
measure: Part 1, 2 and 3: Number of Participants With Anti-PDR001 Antibodies
timeFrame: Up to approximately 5 years
measure: Japan Safety Run-in: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: 28 days
measure: Japan Safety Run-in: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: Up to 0.7 years
measure: All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NIR178
timeFrame: 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
measure: All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NIR178
timeFrame: 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
measure: All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NIR178
timeFrame: 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
measure: All Study Parts: Maximum Observed Plasma Concentration (Cmax) of NJI765 (NIR178 Metabolite)
timeFrame: 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
measure: All Study Parts: Time to Reach Maximum Plasma Concentration (Tmax) of NJI765 (NIR178 Metabolite)
timeFrame: 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
measure: All Study Parts: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of NJI765 (NIR178 Metabolite)
timeFrame: 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
measure: All Study Parts: Maximum Observed Serum Concentration (Cmax) of PDR001
timeFrame: 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
measure: All Study Parts: Time to Reach Maximum Serum Concentration (Tmax) of PDR001
timeFrame: 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
measure: All Study Parts: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001
timeFrame: 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
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: University of California, Los Angeles
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute .
state: Florida
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Houston
country: United States
facility: MD Anderson Cancer Center/University of Texas
state: Texas
city: Madison
country: United States
facility: The University of Wisconsin
state: Wisconsin
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Blacktown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Salzburg
country: Austria
facility: Novartis Investigative Site
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Brno
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Marseille
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: St. Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
References: