A Study of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)

• ClinicalTrials.gov Identifier: NCT02900664
• Recruitment Status: Completed
• First Posted: September 14, 2016
• Last Update Posted: March 29, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 17, 2016
• First Posted Date: September 14, 2016
• Last Update Posted Date: March 29, 2022
• Actual Study Start Date: August 23, 2016
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2016)

• Frequency of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: Throughout the study at every visit, an average of 1 year ]
• Changes between baseline and post-baseline laboratory parameters and vital signs. [ Time Frame: Baseline and throughout the study at every visit, an average of 1 year ]
• Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only) [ Time Frame: During the first two cycles; Cycle = 28 days ]
• Frequency of dose interruptions [ Time Frame: Throughout the study at every visit, an average of 1 year ]
• Dose intensities [ Time Frame: Throughout the study at every visit, an average of 1 year ]
• Severity of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) as a measure of safety [ Time Frame: Throughout the study at every visit, an average of 1 year ]
• Frequency of dose reductions [ Time Frame: Throughout the study at every visit, an average of 1 year ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 9, 2016)

• Key secondary: Histopathology of tumor infiltrating lymphocytes (TILs) [ Time Frame: Baseline and approximately after 2 cycles of treatment and at disease progression; Cycle = 28 days ]
• Changes from baseline in electrocardiogram (ECG) parameters [ Time Frame: Baseline and end of treatment, an average of 1 year ]
• Best overall response (BOR) [ Time Frame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Progression free survival (PFS) per irRC and RECIST v1.1 [ Time Frame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Treatment Free Survival (TFS) [ Time Frame: T1: Every 2 cycles until the start of T2. T2: Every 2 cycles until cycle 3 and then every 3 cycles until PD; cycle = 28 days ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Presence and/or concentration of anti-PDR001 antibodies. [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Serum concentration of PDR001, canakinumab, CJM112 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Plasma concentrations of trametinib and EGF816 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Key secondary: Histopathology of myeloid cell infiltrate by IHC (such as CD8, FoxP3 and myeloid markers as appropriate). [ Time Frame: Baseline and approximately after 3 cycles of treatment and at disease progression; cycle = 28 days ]
• PK parameters (Eg. TMax) of EGF816 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• PK parameters (Eg. TMax) of trametinib [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• PK parameter (Eg. TMax) of PDR001 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• PK parameters (Eg. TMax) of canakinumab [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• PK parameters (Eg. TMax) of CJM112 [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Presence and/or concentration of anti-canakinumab antibodies. [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2
• Presence and/or concentration of anti-CJM112 antibodies. [ Time Frame: Cycle 1 through cycle 6 in treatment period 1 and 2 (an average of 1 year) ]
  T1: treatment period 1 (6 cycles of treatment) T2: treatment period 2

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)
• Official Title: Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability and Pharmacodynamics (PD) of PDR001 in Combination With CJM112, EGF816, Ilaris® (Canakinumab) or Mekinist® (Trametinib)
• Brief Summary: The purpose of this study was to combine the PDR001 checkpoint inhibitor with each of four agents with immunomodulatory activity to identify the doses and schedule for combination therapy and to preliminarily assess the safety, tolerability, pharmacological and clinical activity of these combinations.
• Detailed Description: This was a Phase Ib, multi-center, open-label study, to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 in combination with canakinumab, CJM112, trametinib and EGF816 and single agent (s.a.) canakinumab in subjects with Triple Negative Breast Cancer (TNBC), Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC). The study comprised a dose escalation part for combination treatments only, followed by a dose expansion part.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Cancer, Triple Negative Breast Cancer, NSCLC - Adenocarcinoma

Intervention

• Biological: PDR001
  Powder for solution for infusion
  Other Name: Spartalizumab/PDR001
• Biological: ACZ885
  Solution for injection
  Other Name: canakinumab
• Biological: CJM112
  Solution for infusion
• Drug: TMT212
  Tablets
  Other Name: trametinib
• Drug: EGF816
  Tablets
  Other Name: Nazartinib

Study Arms

• Experimental: PDR + ACZ 100mg Q8W
  PDR + ACZ 100mg Q8W
  Interventions:

  • Biological: PDR001
  • Biological: ACZ885
• Experimental: PDR + ACZ 300mg Q8W
  PDR + ACZ 300mg Q8W
  Interventions:

  • Biological: PDR001
  • Biological: ACZ885
• Experimental: PDR + ACZ RDE TNBC
  PDR + ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)
  Interventions:

  • Biological: PDR001
  • Biological: ACZ885
• Experimental: PDR + ACZ RDE NSCLC
  PDR + ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)
  Interventions:

  • Biological: PDR001
  • Biological: ACZ885
• Experimental: PDR + ACZ RDE CRC
  PDR + ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)
  Interventions:

  • Biological: PDR001
  • Biological: ACZ885
• Experimental: PDR + CJM 25mg Q4W
  PDR + CJM 25mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 75mg Q4W
  PDR + CJM 75mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 225mg Q4W
  PDR + CJM 225mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 450mg Q4W
  PDR + CJM 450mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 450mg Q2W
  PDR + CJM 450mg Q2W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 900mg Q4W
  PDR + CJM 900mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 900mg Q2W
  PDR + CJM 900mg Q2W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + CJM 1200mg Q4W
  PDR + CJM 1200mg Q4W
  Interventions:

  • Biological: PDR001
  • Biological: CJM112
• Experimental: PDR + TMT 0.5mg QD
  PDR + TMT 0.5mg QD
  Interventions:

  • Biological: PDR001
  • Drug: TMT212
• Experimental: PDR + TMT 1mg QD
  PDR + TMT 1mg QD
  Interventions:

  • Biological: PDR001
  • Drug: TMT212
• Experimental: PDR + TMT 1mg QD, 3 Weeks on/1 Week off
  PDR + TMT 1mg QD, 3 Weeks on/1 Week off
  Interventions:

  • Biological: PDR001
  • Drug: TMT212
• Experimental: PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
  PDR + TMT 1.5 mg QD, 2 Weeks on/2 Weeks off
  Interventions:

  • Biological: PDR001
  • Drug: TMT212
• Experimental: PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
  PDR + TMT 1.5 mg QD, 3 Weeks on/1 Week off
  Interventions:

  • Biological: PDR001
  • Drug: TMT212
• Experimental: PDR + EGF816 25mg QD
  PDR + EGF816 25mg QD
  Intervention: Drug: EGF816
• Experimental: PDR + EGF816 50mg QD
  PDR + EGF816 50mg QD
  Intervention: Drug: EGF816
• Experimental: s.a. ACZ RDE TNBC
  Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Triple Negative Breast Cancer (TNBC)
  Intervention: Biological: ACZ885
• Experimental: s.a. ACZ RDE NSCLC
  Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Non-Small Cell Lung Cancer (NSCLC)
  Intervention: Biological: ACZ885
• Experimental: s.a. ACZ RDE CRC
  Single agent (s.a.) ACZ Recommended Dose for Expansion (RDE) Colorectal Cancer (CRC)
  Intervention: Biological: ACZ885

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 15, 2022): 283
• Original Estimated Enrollment (submitted: September 9, 2016): 432
• Actual Study Completion Date: March 17, 2021
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1, who have progressed despite standard therapy or are intolerant to standard therapy, and for whom no effective therapy is available.

Patients must fit into one of the following groups:

• Colorectal cancer (CRC) (not mismatch repair deficient by local assay including PCR and/or immunohistochemistry)
• Non-small cell lung cancer (NSCLC) (adenocarcinoma)
• Triple Negative Breast Cancer (TNBC) (D
• ECOG Performance Status ≤ 2
• Patient 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 baseline, and again during therapy on this study.
• Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to prior PD-1- or PD-L1-directed therapy did not lead to discontinuation of therapy.
• Written informed consent must be obtained prior to any screening procedures other than procedures performed as part of standard of care.

Exclusion Criteria:

• Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks.
• History of severe hypersensitivity reactions to other monoclonal antibodies.
• Out of range laboratory values for measures of hepatic and renal function, electrolytes and blood counts
• Impaired cardiac function or clinically significant cardiac disease.
• Patients with active, known or suspected autoimmune disease.
• Human Immunodeficiency Virus infection at screening.
• Escalation part: Active Hepatitis B (HBV) or Hepatitis C (HCV) virus infection at screening.

Expansion part: Patients with active HBV or HCV are excluded, excepting those patients undergoing treatment for HBV or HCV.

• Malignant disease, other than that being treated in this study.
• Recent systemic anti-cancer therapy
• Active infection requiring systemic antibiotic therapy.
• Patients requiring chronic treatment with systemic steroid therapy, other than replacement dose steroids in the setting of adrenal insufficiency or treatment with low, stable dose of steroid (<10mg/ day prednisone or equivalent) for stable CNS metastatic disease.
• Patients receiving systemic treatment with any immunosuppressive medication, excepting the above
• Use of any live vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
• Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment.
• Presence of ≥ CTCAE grade 2 toxicity (except alopecia and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
• Recent use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF)

Additional exclusion criteria for Combination arm PDR001+canakinumab and single-agent canakinumab

• Patients with tuberculosis (TB). Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
• Patients who have been infected with HBV or HCV including those with inactive disease.

Additional exclusion criteria for Combination arm PDR001+CJM112

• Patients with TB. Note: Patient with latent TB may be eligible based on the investigator's benefit-risk assessment.
• Patients with history of and/or active inflammatory bowel disease.
• Active skin or soft tissue infection including cellulitis, erysipelas, impetigo, furuncle,carbuncle, abscess, or fasciitis.
• Active candida infection, including mucocutaneous infection or history of invasive candidiasis.

Additional exclusion criteria for Combination arm PDR001+trametinib

• Patients with history of retinal vein oclusion.
• Patients with history of interstitial lung disease or pneumonitis.
• Patients with cardiomyopathy and/or LVEF < LLN.
• Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners.
• Hemoglobin (Hgb) < 9 g/dL without growth factor or transfusion support
• Women of child-bearing potential using hormonal contraception, unless an additional contraception method is also used according to the Mekinist® label.

Additional exclusion criteria for Combination arm PDR001+EGF816

• NSCLC patients with EGFR mutant tumors.
• Strong inhibitors and strong inducers of CYP3A4 should not be used concomitantly.
• Patients with history of interstitial lung disease.
• Patients who have been infected with HBV or HCV including those with inactive disease.
• Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral combination partners
• Patients cannot have received radiotherapy to lung fields within 6 months of study treatment start.

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: Belgium, Canada, France, Israel, Italy, Singapore, Spain, Taiwan, United States

Administrative Information

• NCT Number: NCT02900664
• Other Study ID Numbers: CPDR001X2103; 2016-000633-49 ( 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: No

• 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

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2022