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

• ClinicalTrials.gov Identifier: NCT03207867
• Recruitment Status: Active, not recruiting
• First Posted: July 5, 2017
• Last Update Posted: January 20, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 19, 2017
• First Posted Date: July 5, 2017
• Last Update Posted Date: January 20, 2023
• Actual Study Start Date: August 28, 2017
• Estimated Primary Completion Date: February 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 19, 2020)

• Determine the overall response rate [ Time Frame: Every 8 weeks for first 40 weeks ]
  Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)
• Determine the overall response rate [ Time Frame: Every 12 weeks after the first 40 weeks until disease progression or study discontinuation (an average of 6 months) ]
  Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)
• Determine the overall response rate [ Time Frame: Baseline ]
  Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL), or PCWG3 criteria (for mCRPC)

Original Primary Outcome Measures (submitted: June 30, 2017)

• Determine the overall response rate [ Time Frame: Every 8 weeks for first 40 weeks ]
  Response assessed by RECIST 1.1, irRC and Cheson as applicable
• Determine the overall response rate [ Time Frame: Every 12 weeks after the first 40 weeks until disease progression or study discontinuation (an average of 6 months) ]
  Response assessed by RECIST 1.1, irRC and Cheson as applicable
• Determine the overall response rate [ Time Frame: Baseline ]
  Response assessed by RECIST 1.1, irRC and Cheson as applicable

Current Secondary Outcome Measures (submitted: February 23, 2021)

• Determine the disease control rate (DCR) [ Time Frame: Baseline ]
  Proportion of patients with a best overall response of CR or PR or SD
• Determine the duration of response (DoR) [ Time Frame: Baseline ]
  Time from first documented response to disease progression
• Determine the overall survival rate (OR) [ Time Frame: Every 12 weeks until end of study for at least 24 months from the start date of the study treatment ]
  Time from start of treatment to date of death due to any reason
• Progression free survival (PFS) [ Time Frame: Baseline ]
  Time from start of treatment to date of the first documented progression or death in months
• Safety and tolerability of the NIR178 and PDR001 combination [ Time Frame: Date of consent to end of study (An average of 24 months) ]
  Type, frequency, and severity of AEs and SAEs; Frequency of dose interruptions, reductions and discontinuation, Dose intensity
• Characterize changes in the immune infiltrate in tumors [ Time Frame: Screening ]
  Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
• Presence and/or concentration of anti-PDR001 antibodies [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Presence and/or concentration of anti-PDR001 antibodies
• Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of NIR178 and its metabolites
• Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (PDR001) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Plasma concentration Vs Time profiles (NIR178) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Plasma concentration Vs Time profiles (PDR001) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Peak plasma concentration- Cmax (NIR178) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Peak plasma concentration- Cmax (PDR001) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Time of maximum concentration observed- Tmax (NIR178) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Time of maximum concentration observed- Tmax (PDR001) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Determine the disease control rate (DCR) [ Time Frame: Every 8 weeks for first 40 weeks ]
  Proportion of patients with a best overall response of CR or PR or SD
• Determine the disease control rate (DCR) [ Time Frame: Every 12 weeks after the first 40 weeks until disease progression ]
  Proportion of patients with a best overall response of CR or PR or SD
• Determine the duration of response (DoR) [ Time Frame: Until study discontinuation (an average of 6 months) ]
  Time from first documented response to disease progression
• Determine the duration of response (DoR) [ Time Frame: Every 8 weeks for first 40 weeks ]
  Time from first documented response to disease progression
• Progression free survival (PFS) [ Time Frame: Until study discontinuation (an average of 6 months) ]
  Time from start of treatment to date of the first documented progression or death in months
• Progression free survival (PFS) [ Time Frame: Every 8 weeks for first 40 weeks ]
  Time from start of treatment to date of the first documented progression or death in months
• Characterize changes in the immune infiltrate in tumors [ Time Frame: Cycle 6 Day 1 ]
  Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
• Characterize changes in the immune infiltrate in tumors [ Time Frame: Cycle 1 Day 8 ]
  Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
• Characterize changes in the immune infiltrate in tumors [ Time Frame: Cycle 2 Day 1 ]
  Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
• Presence and/or concentration of anti-PDR001 antibodies [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Presence and/or concentration of anti-PDR001 antibodies
• Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178 and its metabolites
• Plasma concentration Vs Time profiles (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of NIR178
• Plasma concentration Vs Time profiles (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of PDR001
• Peak plasma concentration- Cmax (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of NIR178
• Peak plasma concentration- Cmax (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of PDR001
• Time of maximum concentration observed- Tmax (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of NIR178
• Time of maximum concentration observed- Tmax (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1 ]
  Plasma concentration time profiles of PDR001
• Determine the disease control rate (DCR) [ Time Frame: Until study discontinuation (an average of 6 months) ]
  Proportion of patients with a best overall response of CR or PR or SD
• Determine the duration of response (DoR) [ Time Frame: Every 12 weeks after the first 40 weeks until disease progression ]
  Proportion of patients with a best overall response of CR or PR or SD
• Progression free survival (PFS) [ Time Frame: Every 12 weeks after the first 40 weeks until disease progression ]
  Time from start of treatment to date of the first documented progression or death in months

Original Secondary Outcome Measures (submitted: June 30, 2017)

• Disease control rate (DCR) [ Time Frame: Baseline, every 8 weeks for first 40 weeks and every 12 weeks thereafter until disease progression or study discontinuation (an average of 6 months) ]
  Proportion of patients with a best overall response of CR or PR or SD
• Duration of response (DoR) [ Time Frame: Baseline, every 8 weeks for first 40 weeks and every 12 weeks thereafter until disease progression or study discontinuation (an average of 6 months) ]
  Time from first documented response to disease progression
• Overall survival rate (OR) [ Time Frame: Every 12 weeks until end of study for at least 24 months from the start date of the study treatment ]
  Time from start of treatment to date of death due to any reason
• Progression free survival (PFS) [ Time Frame: Baseline, every 8 weeks for first 40 weeks and every 12 weeks thereafter until disease progression or study discontinuation (an average of 6 months) ]
  Time from start of treatment to date of the first documented progression or death in months
• Safety and tolerability of the NIR178 and PDR001 combination [ Time Frame: Date of consent to end of study (An average of 24 months) ]
  Type, frequency, and severity of AEs and SAEs; Frequency of dose interruptions, reductions and discontinuation, Dose intensity
• Characterize changes in the immune infiltrate in tumors [ Time Frame: Screening, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 6 Day 1 ]
  Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)
• Presence and/or concentration of anti-PDR001 antibodies [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Presence and/or concentration of anti-PDR001 antibodies
• Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178 and its metabolites
• Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Plasma concentration Vs Time profiles (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Plasma concentration Vs Time profiles (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Peak plasma concentration- Cmax (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Peak plasma concentration- Cmax (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001
• Time of maximum concentration observed- Tmax (NIR178) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of NIR178
• Time of maximum concentration observed- Tmax (PDR001) [ Time Frame: Starting from the first dose of study treatment to Cycle 6 Day 1, End of treatment and as needed (an average of 6 months) ]
  Plasma concentration time profiles of PDR001

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

The study has three parts: part 1: Multi-arm Bayesian adaptive signal finding design in solid tumors and diffuse large B cell lymphoma (DLBCL); part 2: NIR178 schedule exploration in NSCLC; part 3: Further evaluation of intermittent or continuous dosing schedules of NIR178 in combination with PDR001 in additional tumor types, if part 2 identifies an intermittent or continuous dosing schedule of NIR178 as warranting further exploration. In addition, a separate safety run-in part will be conducted in Japan in order to adequately characterize the safety and pharmacokinetic profiles of NIR178 as a single-agent and in combination with PDR001.

Parts 1 and 2 and the safety run-in in Japan will enroll in parallel. Part 3 will be opened based on the results from part 1 and part 2 and may enroll in parallel with Part 1.

Patients enrolled in this study will receive NIR178 either BID continuously or based on the assigned intermittent schedule within 60 minutes prior to PDR001 infusion. PDR001 will be administered via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle is 28 days. Patients enrolled in the Japanese safety run-in part will receive NIR178 as single agent for the first cycle (28 days). If the patients complete cycle 1 without experiencing DLTs, they will initiate combination therapy with PDR001 starting cycle 2 onwards, and continue at the same dose of NIR178. An additional cohort in the Japanese safety run-in part of the study will receive NIR178 in combination with PDR001 starting with Cycle 1. If the patients complete cycle 1 without experiencing DLTs, they will continue to receive combination treatment.

Patients will receive 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
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• Drug: NIR178
  NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.
• Drug: PDR001
  PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle

Study Arms

• Experimental: NIR178 + PDR001
  Part 1: all patients will receive NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 will enroll 9 different tumor types.
  Interventions:

  • Drug: NIR178
  • Drug: PDR001
• Experimental: NIR178 BID Intermittent + PDR001
  Three different dosing schedules of NIR178 will be explored.
  Interventions:

  • Drug: NIR178
  • Drug: PDR001
• Experimental: Part 3
  Initiation of part 3 will depend on results from parts 1 and 2 and will use a film-coated tablet of NIR178.
  Interventions:

  • Drug: NIR178
  • Drug: PDR001
• Experimental: Japanese safety run-in part
  Two different dosing schedules of NIR178 will be explored.
  Interventions:

  • Drug: NIR178
  • Drug: PDR001

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 11, 2022): 317
• Original Estimated Enrollment (submitted: June 30, 2017): 300
• Estimated Study Completion Date: February 15, 2023
• Estimated Primary Completion Date: February 15, 2023 (Final data collection date for primary outcome measure)

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.

Other protocol-defined exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Czechia, France, Germany, Italy, Japan, Netherlands, Singapore, Spain, Switzerland, Taiwan, United States

Administrative Information

• NCT Number: NCT03207867
• Other Study ID Numbers: CNIR178X2201; 2017-000241-49 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: January 2023