Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03207867
Recruitment Status : Recruiting
First Posted : July 5, 2017
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( 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.

Condition or disease Intervention/treatment Phase
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 Drug: NIR178 Drug: PDR001 Phase 2

Detailed Description:

The study has four 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 dosing schedules of NIR178 in combination with PDR001 in additional tumor types, if part 2 identifies an intermittent dosing schedule of NIR178 as warranting further exploration; part 4: 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.

Parts 1, 2 and 4 will enroll in parallel. Part 3 will be opened based on the results from part 2.

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.

Patients will receive treatment with the combination until disease progression (assessed by investigator per immune-related response criteria (irRC) 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 285 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 28, 2017
Estimated Primary Completion Date : June 27, 2019
Estimated Study Completion Date : November 6, 2020


Arm Intervention/treatment
Experimental: NIR178 + PDR001
Part 1: all patients will receive NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 will enroll 8 different tumor types.
Drug: NIR178
NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.

Drug: PDR001
PDR001 is a human monoclonal antibody (MAb) administered day 1 of each cycle

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

Experimental: Part 3
Initiation of part 3 will depend on results from parts 1 and 2.
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

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




Primary Outcome Measures :
  1. Determine the overall response rate [ Time Frame: Every 8 weeks for first 40 weeks ]
    Response assessed by RECIST v1.1 (for solid tumors) or Cheson (for DLBCL)

  2. 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) or Cheson (for DLBCL)

  3. Determine the overall response rate [ Time Frame: Baseline ]
    Response assessed by RECIST v1.1 (for solid tumors) or Cheson (for DLBCL)


Secondary Outcome Measures :
  1. Determine the disease control rate (DCR) [ Time Frame: Baseline ]
    Proportion of patients with a best overall response of CR or PR or SD

  2. Determine the duration of response (DoR) [ Time Frame: Baseline ]
    Time from first documented response to disease progression

  3. 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

  4. Progression free survival (PFS) [ Time Frame: Baseline ]
    Time from start of treatment to date of the first documented progression or death in months

  5. 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


  6. Characterize changes in the immune infiltrate in tumors [ Time Frame: Screening ]
    Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Peak plasma concentration- Cmax (NIR178) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
    Plasma concentration time profiles of NIR178

  13. Peak plasma concentration- Cmax (PDR001) [ Time Frame: End of treatment and as needed (an average of 6 months) ]
    Plasma concentration time profiles of PDR001

  14. 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

  15. 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

  16. 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

  17. 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

  18. Determine the duration of response (DoR) [ Time Frame: Until study discontinuation (an average of 6 months) ]
    Time from first documented response to disease progression

  19. Determine the duration of response (DoR) [ Time Frame: Every 8 weeks for first 40 weeks ]
    Time from first documented response to disease progression

  20. 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

  21. 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

  22. 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)

  23. 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)

  24. Characterize changes in the immune infiltrate in tumors [ Time Frame: Cycle 3 Day 1 ]
    Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) or melanoma
  • 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 advanced/metastatic NSCLC and one additional tumor type based on emerging data from part 1 of the study.

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.

o Part 4: Safety run-in part in Japanese patients can enroll any tumor type included in part 1 and 2.

The collection of recent sample is permitted under the following conditions (both must be met):

  • Biopsy was collected ≤ 3 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, specifically including the following, 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 must have received a prior taxane-containing regimen.

Patients with DLBCL should be limited to those with no available therapies of proven clinical benefit

o Patients should have had prior autologous hematopoietic stem cell transplantation (auto-HSCT) or determined to be ineligible for auto-HSCT.

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.

Other protocol-defined inclusion criteria may apply.

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 Participation in another clinical study with an investigational product during the last 21 days prior to starting on treatment.

Other protocol-defined exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03207867


Contacts
Layout table for location contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

  Show 20 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals

Layout table for additonal information
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03207867     History of Changes
Other Study ID Numbers: CNIR178X2201
2017-000241-49 ( EudraCT Number )
First Posted: July 5, 2017    Key Record Dates
Last Update Posted: May 6, 2019
Last Verified: May 2019
Individual Participant Data (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


Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Immunotherapy, A2aR, PDR001, NIR178, NSCLC, solid tumors

Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Carcinoma, Non-Small-Cell Lung
Pancreatic Neoplasms
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Head and Neck Neoplasms
Triple Negative Breast Neoplasms
Carcinoma, Renal Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Breast Neoplasms
Breast Diseases
Skin Diseases