MK-3475-174 (IMDZ-G142)

Merck Sharp & Dohme Corp.

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

No

No

No

Final

01 Aug 2019

Yes

01 Aug 2019

Yes

01 Aug 2019

Yes

This is a Phase 1/2 open label trial of G100 in participants with low grade Non-Hodgkin's Lymphoma (NHL). G100 is composed of glucopranosyl lipid A in a stable emulsion and is a potent TLR4 (toll-like receptor-4) agonist. G100 will be administered by direct injection (intratumorally) into tumors of low grade NHL with or without standard low dose radiation therapy. Preclinical models and clinical studies in other cancers such as Merkel cell carcinoma have demonstrated that G100 administered in this manner can alter the tumor microenvironment, activate dendritic cells, T cells and other immune cells and induce systemic anti-tumor immune responses. In this trial, the safety, immunogenicity, and preliminary clinical efficacy of G100 will be examined alone or with pembrolizumab.

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

03 Feb 2016

Yes

Yes

United States: 41

United Kingdom: 2

France: 1

Spain: 8

52

11

0

0

0

0

0

0

31

21

0

Overall Study (overall period)

Randomised - controlled

Yes

G100

Injection

Intratumoral use

G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

G100

Injection

Intratumoral use

G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

G100

Injection

Intratumoral use

G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

G100

Injection

Intratumoral use

G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

Pembrolizumab

Solution for infusion

Intravenous use

Pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

G100

Injection

Intratumoral use

G100 at 20 μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.

G100

Injection

Intratumoral use

G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

Local radiation

Radionuclide generator

Local use

Radiation of a tumor in the radiation field on Day 1.

Pembrolizumab

Solution for infusion

Intravenous use

Pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

G100

Injection

Intratumoral use

G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

Part 1: Local Radiation + G100 5μg/lesion

Part 1: Local Radiation + G100 10μg/lesion

Part 2: Local Radiation + G100 10μg/lesion

Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg

Part 2: Local Radiation, G100 20μg/lesion in Large Tumors

Part 3: Local Radiation + G100 20μg/lesion

Part 4: G100 20μg/lesion and Pembrolizumab 200mg

Part 1: Local Radiation + G100 5μg/lesion

Part 1: Local Radiation + G100 10μg/lesion

Part 2: Local Radiation + G100 10μg/lesion

Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg

Part 2: Local Radiation, G100 20μg/lesion in Large Tumors

Part 3: Local Radiation + G100 20μg/lesion

Part 4: G100 20μg/lesion and Pembrolizumab 200mg

An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation.

Primary

Up to approximately 42 months

An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation.

Primary

Up to approximately 105 weeks

Overall response rate was defined as participants with best overall response of immune-related complete response (irCR) or immune-related partial response (irPR). irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations are not determinants of progressive disease by themselves. An irCR is the disappearance of all lesions, and no new lesions; an irPR is a ≥50% drop in tumour burden from baseline; and immune related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else is considered immune-related Stable Disease (irSD). Tumor staging using bi-dimensional measurements was performed by CT or MRI. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post baseline disease assessment.

Secondary

Up to approximately 42 months

Clinical benefit rate (CBR) was defined as the number and percent of participants with best overall response of Immune related Response Criteria (irRC); complete response, partial response or stable disease (irCR+irPR+irSD). irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations and are not determinants of progressive disease by themselves. irCR is the disappearance of all lesions, and no new lesions; irPR is a ≥50% drop in tumor burden from baseline; and immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Everything else is considered irSD. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to approximately 42 months

Clinical benefit rate (CBR) was all participants with best overall response of complete response, partial response or stable disease (CR+PR+SD). The IWG criteria (Cheson et al 2014) for a CR is a complete radiologic response (target nodes/nodal masses must regress to ≤ 1.5 cm in longest transverse diameter (LDi), no extralymphatic sites of disease, and no new tumors. A PR is a ≥ 50% decrease in SPD (sum of the product of the perpendicular diameters for multiple tumors) of up to 6 target measurable nodes and extranodal sites, spleen must have regressed by > 50% in length beyond normal, and no new tumors. Stable disease is a < 50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met, and no new tumors. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to approximately 42 months

Duration of response (DOR) was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed response using irRC and the date of disease progression (PD) or death for any cause, whichever occurs first. DOR in months was calculated as: (date of PD or death minus date of first confirmed/unconfirmed irCR/CR or irPR/PR + 1)/30.4375. DOR analysis included only participants with confirmed/unconfirmed response of irCR/irPR using irRC. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Median DOR with the corresponding two-sided 95% CI was estimated using the Kaplan-Meier method in each treatment group. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation and had a confirmed/unconfirmed response of irCR/irPR using irRC.

Secondary

Up to approximately 42 months

Duration of clinical benefit was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed best response using irRC and the date of progressive disease (PD) or death for any cause, whichever occurred first. Duration of clinical benefit in months was calculated as: (date of PD or death – date of first confirmed/unconfirmed irCR/irPR or irSD + 1)/30.4375. Duration of clinical benefit included only participants with confirmed/unconfirmed response of irCR/irPR or irSD using irRC. Participants without progression, symptomatic deterioration, or death were censored at the date of the last tumor assessment. Median duration of clinical benefit and 95% CI were estimated using the Kaplan Meier method. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation and had a confirmed/unconfirmed response of irCR/irPR or irSD using irRC.

Secondary

Up to approximately 42 months

PFS was defined as time from date of first study treatment to date of first disease progression (a ≥25% increase in tumor burden from the lowest level recorded) by irRC criteria, symptomatic deterioration, or death due to any cause, whichever occurred first. Participants without progression, symptomatic deterioration, or death were censored at the date of the last tumor assessment. Progression-free survival in months is calculated as: (date of first progression, symptomatic deterioration, or death [any reason] – date of first dose +1)/30.4375. The irRC modification required a PD confirmation no less than 4 weeks from first documentation of PD. Summary of PFS including median, 95% CI was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to approximately 42 months

Overall Survival (OS) was defined as the time from date of first study treatment to death due to any cause. Overall survival in months was calculated as: ([date of death – date of first dose] +1)/30.4375. Participants who were alive at the end of study were censored at the last date the participant was known to be alive or data analysis cutoff date, whichever was earlier. Summary of OS including median, 95% CI was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to approximately 42 months

Abscopal tumor responses were assessed in non-treated, distal tumor sites. Immune-related Response Criteria irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations are not determinants of progressive disease. An immune-related Complete Response (irCR) is the disappearance of all lesions, and no new lesions; an immune-related Partial Response (irPR) is a ≥50% drop in tumour burden from baseline; and immune related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else was considered immune-related Stable Disease (irSD). Tumor staging by CT or MRI was performed. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post baseline disease assessment.

Secondary

Up to approximately 42 months

Time to Response for CR and PR participants was defined as time from date of first study treatment to the date of CR or PR response first documented. Complete Response (irCR) is the disappearance of all lesions, and no new lesions; an immune-related Partial Response (irPR) is a ≥50% drop in tumor burden from baseline. Time to response in months was calculated as: (date of first CR or PR minus date of first dose +1)/30.4375. Summary of Time to Response including median and range was estimated using Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to 42 months

Time to next treatment was defined as the time from the date of first study treatment to the start date of subsequent therapy after PD. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Participants who did not receive subsequent therapy after PD were censored at the date of last contact or death. Summary of time to next treatment including median and range was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.

Secondary

Up to approximately 42 months

Up to approximately 42 months

The analysis population included all treated participants. Medical Dictionary for Regulatory Activities (MedDRA) terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study treatment were excluded as AEs as considered due to cancer progression. No participant was enrolled or dosed in Part 5.

22.0

Part 2: Local Radiation + G100 10μg/lesion

Part 1: Local Radiation + G100 10μg/lesion

Part 1: Local Radiation + G100 5μg/lesion

Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg

Part 2: Local Radiation, G100 20 μg/lesion in Large Tumors

Part 4: G100 20μg/lesion and pembrolizumab 200mg

Part 3: Local Radiation + G100 20μg/lesion