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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT03172936

Collaborator

(none)

106

Enrollment

Locations

Arms

39.3

Actual Duration (Months)

8.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of MIW815 (ADU-S100) in combination with PDR001.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors and Lymphomas	Drug: MIW815 Biological: PDR001	Phase 1

Detailed Description

This was 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 were explored in two dose escalation groups in accessible cutaneous or subcutaneous lesions. The optional dose confirmation group exploring intratumoral injection of viscerally located lesions was not opened due to the program's early termination.

Group A included patients with accessible solid tumors and lymphomas. This group received 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 included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 i.v. on day 1 of every 28 day cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every 28 day cycle.

Once the dose and dose schedule had been confirmed, the plan was to open the dose expansion part of the study. However, the expansion phase of the study was not opened to enrollment due to the program's early termination.

Study Design

Study Type:

Interventional

Actual Enrollment :

106 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The study was comprised of two treatment arms. Group A included patients with accessible solid tumors and lymphomas. This group received 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 included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 intravenous on day 1 of every 28 day cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every 28 day cycle. Once the maximum tolerated dose and/or recommended dose for expansion had been determined, the plan was to open the expansion part of the study. However, the dose expansion phase of the study was not opened to enrollment due to the program's early termination.The study was comprised of two treatment arms. Group A included patients with accessible solid tumors and lymphomas. This group received 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 included patients with accessible solid tumors and lymphomas. This group received a fixed dose of PDR001 intravenous on day 1 of every 28 day cycle and an intratumoral injection of MIW815 (ADU-S100) on day 1 of every 28 day cycle. Once the maximum tolerated dose and/or recommended dose for expansion had been determined, the plan was to open the expansion part of the study. However, the dose expansion phase of the study was not opened to enrollment due to the program's early termination.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Sep 8, 2017

Actual Primary Completion Date :

Dec 18, 2020

Actual Study Completion Date :

Dec 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dosing Schedule A Patients were treated with MIW815 (ADU-S100) via intratumoral injection for 3 weeks followed by one week off in combination with a fixed intravenous dose of PDR001 given once per month	Drug: MIW815 MIW 815 (ADU-S100) is a STING agonist Biological: PDR001 PDR001 is an anti-PD-1 antibody
Experimental: Dosing Schedule B Patients were 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	Drug: MIW815 MIW 815 (ADU-S100) is a STING agonist Biological: PDR001 PDR001 is an anti-PD-1 antibody

Arm

Intervention/Treatment

Experimental: Dosing Schedule A

Patients were treated with MIW815 (ADU-S100) via intratumoral injection for 3 weeks followed by one week off in combination with a fixed intravenous dose of PDR001 given once per month

Drug: MIW815

MIW 815 (ADU-S100) is a STING agonist

Biological: PDR001

PDR001 is an anti-PD-1 antibody

Experimental: Dosing Schedule B

Patients were 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

Drug: MIW815

MIW 815 (ADU-S100) is a STING agonist

Biological: PDR001

PDR001 is an anti-PD-1 antibody

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicities (DLTs) [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

Secondary Outcome Measures

AUC inf [36 months]
The area under the concentration-time curve extrapolated to infinity (mass*time/volume)
AUC last [36 months]
The area under the concentration (AUC) -time curve calculated to the last quantifiable concentration point (mass* time/volume)
AUC tau [36 months]
Area under the concentration-time curve calculated to the end of the dosing interval (tau) (mass* time/volume)
Tmax [36 months]
The time to reach the maximum observed concentration (time)
Cmax [36 months]
The maximum observed concentration (Cmax) following dose administration (mass/volume)
Lambda_z [36 months]
Terminal elimination rate constant (1/time)
CL/F [36 months]
Apparent systemic clearance of drug from the plasma (volume x time -1)
T1/2 [36 months]
Elimination half-life, determined as 0.693/Lambda_z (time)
Vz/F [36 months]
Apparent volume of distribution during the terminal elimination phase (volume)
Best overall response (BOR) [36 months]
Best overall response will be summarized
Overall response rate (ORR) [36 months]
Overall response rate will be summarized with accompanying 90% exact binomial confidence interval (CI).
Progression free survival (PFS) [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) [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) [36 months]
Time To Response is the time from first dose to first documented response (CR or PR). TTR will be summarized
Duration of Response (DOR) [36 months]
Duration of response is defined as the time from the date of the first documented response (CR or PR), to the date of first documented progression, or death due to study indication. Estimates will use Kaplan-Meier method
Tumor infiltrating lymphocytes (TIL) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic and Research Institute	Los Angeles	California	United States	90025
2	Novartis Investigative Site	Chicago	Illinois	United States	60637
3	MD Anderson Cancer Center	Houston	Texas	United States	77030
4	Seattle Cancer Care Alliance	Seattle	Washington	United States	98105
5	Novartis Investigative Site	North Sydney	New South Wales	Australia	2060
6	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
7	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
8	Novartis Investigative Site	Essen		Germany	45147
9	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
10	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
11	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
12	Novartis Investigative Site	Zurich		Switzerland	8091