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

NCT03207867 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: CNIR178X22012017-000241-49
• Study Type: interventional
• Target: 315
• Locations: 14 countries
• Sites: 20

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.

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (48)

• Part 1: Overall Response Rate (ORR) Per iRECIST for Solid Tumors

  Up to 3.9 years

• Part 2: Overall Response Rate (ORR) Per iRECIST for Solid Tumors

  Up to 4.7 years

• Part 3: Overall Response Rate (ORR) Per iRECIST for Solid Tumors

  Up to 0.5 years

• Part 1: Mean Percentage Change in PSA From Baseline

  Baseline, up to 0.8 years

• Part 1: Disease Control Rate (DCR) Per RECIST v1.1 for Solid Tumors

  Up to 3.9 years

Study Arms (4)

NIR178 + PDR001

EXPERIMENTAL

Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types.

Drug: NIR178; Drug: PDR001

NIR178 BID Intermittent + PDR001

EXPERIMENTAL

Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001

Drug: NIR178; Drug: PDR001

Part 3

EXPERIMENTAL

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; Drug: PDR001

Japanese safety run-in part

EXPERIMENTAL

Different dosing schedules of NIR178 were explored.

Drug: NIR178; Drug: PDR001

Interventions

NIR178 DRUG

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.

Also known as: taminadenant

Japanese safety run-in part; NIR178 + PDR001; NIR178 BID Intermittent + PDR001; Part 3

PDR001 DRUG

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).

Also known as: spartalizumab

Japanese safety run-in part; NIR178 + PDR001; NIR178 BID Intermittent + PDR001; Part 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (21)

University of California, Los Angeles

Santa Monica, California, 90904, United States

Location

H Lee Moffitt Cancer Center and Research Institute .

Tampa, Florida, 33612, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21205, United States

Location

MD Anderson Cancer Center/University of Texas

Houston, Texas, 77030, United States

Location

The University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Novartis Investigative Site

CABA, Buenos Aires, C1426ANZ, Argentina

Location

Novartis Investigative Site

Blacktown, New South Wales, 2148, Australia

Location

Novartis Investigative Site

Salzburg, 5020, Austria

Location

Novartis Investigative Site

Liège, 4000, Belgium

Location

Novartis Investigative Site

Brno, Czech Republic, 656 53, Czechia

Location

Novartis Investigative Site

Marseille, 13273, France

Location

Novartis Investigative Site

Cologne, 50937, Germany

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Napoli, 80131, Italy

Location

Novartis Investigative Site

Koto Ku, Tokyo, 135 8550, Japan

Location

Novartis Investigative Site

Rotterdam, 3075 EA, Netherlands

Location

Novartis Investigative Site

Singapore, 168583, Singapore

Location

Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

Location

Novartis Investigative Site

Sankt Gallen, 9007, Switzerland

Location

Novartis Investigative Site

Taipei, 10002, Taiwan

Location

Related Links

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

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Pancreatic Neoplasms; Head and Neck Neoplasms; Spinocerebellar Degenerations; Triple Negative Breast Neoplasms; Melanoma

Interventions

spartalizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 19, 2017
• First Posted: July 5, 2017
• Study Start: August 28, 2017
• Primary Completion: February 13, 2023
• Study Completion: February 14, 2023
• Last Updated: October 9, 2024
• Results First Posted: March 1, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

ES (1); SG (1); AR (1); CH (1); AU (1); NL (1); TW (1); JP (1); DE (2); FR (1); CZ (1); US (5); BE (1); IT (2)