Study of the Safety and Efficacy of MIW815 With PDR001 in Patients With Advanced/Metastatic Solid Tumors or Lymphomas

• ClinicalTrials.gov Identifier: NCT03172936
• Recruitment Status: Active, not recruiting
• First Posted: June 1, 2017
• Last Update Posted: November 6, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 30, 2017
• First Posted Date: June 1, 2017
• Last Update Posted Date: November 6, 2020
• Actual Study Start Date: September 8, 2017
• Estimated Primary Completion Date: December 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 31, 2017)

Incidence of dose limiting toxicities (DLTs) [ Time Frame: 24 months ]

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with the combination of MIW815 (ADU-S100) and PDR001

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 4, 2020)

• AUC last [ Time Frame: 36 months ]
  The area under the concentration (AUC) -time curve calculated to the last quantifiable concentration point (mass* time/volume)
• AUC inf [ Time Frame: 36 months ]
  The area under the concentration-time curve extrapolated to infinity (mass*time/volume)
• Cmax [ Time Frame: 36 months ]
  The maximum observed concentration (Cmax) following dose administration (mass/volume)
• Tmax [ Time Frame: 36 months ]
  The time to reach the maximum observed concentration (time)
• Best overall response (BOR) [ Time Frame: 36 months ]
  Best overall response will be summarized with accompanying 90% exact binomial confidence interval.
• Overall response rate (ORR) [ Time Frame: 36 months ]
  Overall response rate will be summarized with accompanying 90% exact binomial confidence interval.
• Progression free survival (PFS) [ Time Frame: 36 months ]
  The survival function will be estimated using the Kaplan-Meier product limit method. Median duration, with a two-sided Brookmeyer-Crowley 90% confidence interval and Kaplan-Meier estimates of survival proportions will be provided at specified time points.
• Disease control rate (DCR) [ Time Frame: 36 months ]
  The disease control rate is calculated as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease
• Time to response (TTR) [ Time Frame: 36 months ]
  Kaplan-Meier estimates may be provided if sufficient numbers of patients respond.
• Duration of Response (DOR [ Time Frame: 36 months ]
  The duration of response is calculated from the assessment date of the first overall lesion response of CR/PR until one of the following: Date of Death, Date of Progression, Date of last adequate tumor assessment or Date of next scheduled assessment
• Tumor infiltrating lymphocytes (TIL) [ Time Frame: 36 months ]
  Induction of TILs in the injected lesion (local PD effect) and in a non-injected lesion (distal PD effect) will be assessed using paired tumor samples at screening and on-treatment.
• Cytokines [ Time Frame: 36 months ]
  Induction of cytokines in the injected lesion (local PD effect) and in a non-injected lesion (distal PD effect) will be assessed using paired tumor samples at screening and on-treatment.

Original Secondary Outcome Measures (submitted: May 31, 2017)

• AUC last [ Time Frame: 36 months ]
  The area under the concentration (AUC) -time curve calculated to the last quantifiable concentration point (mass* time/volume)
• AUC tau [ Time Frame: 36 months ]
  Area under the concentration-time curve calculated to the end of the dosing interval (tau) (mass* time/volume)
• AUC inf [ Time Frame: 36 months ]
  The area under the concentration-time curve extrapolated to infinity (mass*time/volume)
• Cmax [ Time Frame: 36 months ]
  The maximum observed concentration (Cmax) following dose administration (mass/volume)
• Tmax [ Time Frame: 36 months ]
  The time to reach the maximum observed concentration (time)
• Cmin [ Time Frame: 36 months ]
  Minimum observed plasma concentration (mass/volume)
• Lambda_z [ Time Frame: 36 months ]
  Terminal elimination rate constant (1/time)
• T1/2 [ Time Frame: 36 months ]
  Elimination half-life, determined as 0.693/Lambda_z (time)
• CL/F [ Time Frame: 36 months ]
  Apparent systemic clearance of drug from the plasma (volume x time -1)
• Vz/F [ Time Frame: 36 months ]
  Apparent volume of distribution during the terminal elimination phase (volume)
• Best overall response (BOR) [ Time Frame: 36 months ]
  Best overall response will be summarized with accompanying 90% exact binomial confidence interval.
• Overall response rate (ORR) [ Time Frame: 36 months ]
  Overall response rate will be summarized with accompanying 90% exact binomial confidence interval.
• Progression free survival (PFS) [ Time Frame: 36 months ]
  The survival function will be estimated using the Kaplan-Meier product limit method. Median duration, with a two-sided Brookmeyer-Crowley 90% confidence interval and Kaplan-Meier estimates of survival proportions will be provided at specified time points.
• Disease control rate (DCR) [ Time Frame: 36 months ]
  The disease control rate is calculated as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease
• Time to response (TTR) [ Time Frame: 36 months ]
  Kaplan-Meier estimates may be provided if sufficient numbers of patients respond.
• Tumor infiltrating lymphocytes (TIL) [ Time Frame: 36 months ]
  Induction of TILs in the injected lesion (local PD effect) and in a non-injected lesion (distal PD effect) will be assessed using paired tumor samples at screening and on-treatment.
• Cytokines [ Time Frame: 36 months ]
  Induction of cytokines in the injected lesion (local PD effect) and in a non-injected lesion (distal PD effect) will be assessed using paired tumor samples at screening and on-treatment.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: May 31, 2017)

Change in mutation burden in tumor and in circulation [ Time Frame: 36 months ]

Changes from baseline in DNA tumor sample in injected and distal lesions and in cell free (cf) DNA at end of study treatment.

Descriptive Information

• Brief Title: Study of the Safety and Efficacy of MIW815 With PDR001 in Patients With Advanced/Metastatic Solid Tumors or Lymphomas
• Official Title: A Phase Ib, Open Label, Multicenter Study of the Safety and Efficacy of MIW815 (ADU-S100) Administered by Intratumoral Injection With PDR001 to Patients With Advanced/Metastatic Solid Tumors or Lymphomas
• Brief Summary: The purpose of this study is to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of MIW815 (ADU-S100) in combination with PDR001.

Detailed Description

This is a Phase Ib, multi-center, open-label study to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of MIW815(ADU-S100) in combination with the PD-1 checkpoint inhibitor PDR001. Two different schedules will be explored in two dose escalation groups in accessible cutaneous or subcutaneous lesions, as well as an optional dose confirmation group exploring intratumoral injection of viscerally located lesions.

Group A will include patients with accessible solid tumors and lymphomas. This group will receive a fixed dose of PDR001 i.v. on day 1 of every 28 day cycle and intratumoral injections of MIW815 (ADU-S100) on days 1, 8 and 15 of every 28 day cycle. Group B will include patients with accessible solid tumors and lymphomas. This group will receive a fixed dose of PDR001 i.v. on day 1 of every cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every cycle.

Once the dose and dose schedule has been confirmed, the dose expansion part of the study will open. The main purpose of the expansion part is to further assess the safety and tolerability, as well as preliminary anti-tumor activity, of the study treatment at the maximum tolerated dose and/or recommended dose for expansion. .

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study is comprised of two treatment arms.

Group A will include patients with accessible solid tumors and lymphomas. This group will receive a fixed dose of PDR001 intravenous on day 1 of every 28 day cycle and intratumoral injections of MIW815 (ADU-S100) on days 1, 8 and 15 of every 28 day cycle.

Group B will include patients with accessible solid tumors and lymphomas. This group will receive a fixed dose of PDR001 intravenous on day 1 of every cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every cycle.

Once the maximum tolerated dose and/or recommended dose for expansion is determined, the expansion part of the study will open.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Solid Tumors and Lymphomas

Intervention

• Drug: MIW815
  MIW 815 (ADU-S100) is a STING agonist
• Biological: PDR001
  PDR001 is an anti-PD-1 antibody

Study Arms

• Experimental: Dosing Schedule A
  Patients will be treated with MIW815 (ADU-S100) via intratumoral injection for 3 weeks on followed by one week off in combination with a fixed intravenous dose of PDR001 given once per month
  Interventions:

  • Drug: MIW815
  • Biological: PDR001
• Experimental: Dosing Schedule B
  Patients will be treated with MIW815 (ADU-S100) via intratumoral injection given once a month in combination with a fixed intravenous dose of PDR001 given once per month
  Interventions:

  • Drug: MIW815
  • Biological: PDR001

• Publications *: Gogoi H, Mansouri S, Jin L. The Age of Cyclic Dinucleotide Vaccine Adjuvants. Vaccines (Basel). 2020 Aug 13;8(3). pii: E453. doi: 10.3390/vaccines8030453. Review.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 17, 2020): 106
• Original Estimated Enrollment (submitted: May 31, 2017): 175
• Estimated Study Completion Date: December 18, 2020
• Estimated Primary Completion Date: December 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

ECOG ≤ 1 Willing to undergo tumor biopsies from injected and distal lesions

Must have two biopsy accessible lesions:

Exclusion Criteria:

Symptomatic or untreated leptomeningeal disease. Presence of symptomatic central nervous system metastases Impaired cardiac function or clinically significant cardiac disease Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy.

Active infection requiring systemic antibiotic therapy. Known history of human immunodeficiency virus infection. Active Epstein-Barr virus, hepatitis B virus or hepatitis C virus Malignant disease, other than that being treated in this study

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: Australia, Canada, Germany, Japan, Netherlands, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT03172936
• Other Study ID Numbers: CMIW815X2102J; 2017-000707-25 ( 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

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Nancy Lewis, MD; Novartis

• PRS Account: Novartis
• Verification Date: November 2020