Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Participants With Follicular Non-Hodgkin's Lymphoma (MK-3475-174/IMDZ-G142)

NCT02501473 | Terminated Phase 1 Results DMC FDA Drug

• 4 other identifiers: 3475-174IMDZ-G142MK-3475-1742015-005382-23
• Study Type: interventional
• Target: 52
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Follicular Low Grade Non-Hodgkin's Lymphoma

Keywords

follicular lymphoma; FL; low-grade lymphoma; Non-Hodgkin's Lymphoma; follicular NHL; Marginal Zone

Outcome Measures

Primary Outcomes (2)

• Number of Participants With an Adverse Event (AE)

  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.

  Up to approximately 42 months

• Number of Participants Who Discontinued Study Drug Due to an Adverse Event

  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.

  Up to approximately 105 weeks

Secondary Outcomes (10)

• Overall Response Rate (ORR) by Immune-related Response Criteria (irRC)

  Up to approximately 42 months

• Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC)

  Up to approximately 42 months

• Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria

  Up to approximately 42 months

• Duration of Response (DOR) by Immune-related Response Criteria (irRC)

  Up to approximately 42 months

• Duration of Clinical Benefit by Immune-related Response Criteria (irRC)

  Up to approximately 42 months

Study Arms (8)

Part 1: Local Radiation + G100 5μg/tumor

EXPERIMENTAL

Part 1: Local radiation and G100 \[glucopyranosyl lipid A stable emulsion, GLA-SE\] at 5μg/tumor administered intratumorally (IT) into accessible tumors for up to 8 weeks.

Drug: G100

Part 1: Local Radiation + G100 10μg/tumor

EXPERIMENTAL

Part 1: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks.

Drug: G100

Part 2: Local Radiation + G100 10μg/tumor

EXPERIMENTAL

Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks.

Drug: G100

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

EXPERIMENTAL

Part 2: Local radiation and G100 at 10μg/tumor administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

Drug: G100; Drug: Pembrolizumab

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

EXPERIMENTAL

Part 2: Local radiation and G100 at 20 μg/tumor administered IT into accessible large tumors \[injectable lymphoma mass(es) ≥ 4 cm in total size\] for up to 8 weeks.

Drug: G100

Part 3: Local Radiation + G100 20μg/tumor

EXPERIMENTAL

Part 3: Local radiation and G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks.

Drug: G100

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

EXPERIMENTAL

Part 4: G100 at 20μg/tumor administered IT into accessible tumors for up to 8 weeks and pembrolizumab 200mg IV and administered Q3W for up to 2 years.

Drug: G100; Drug: Pembrolizumab

Part 5: G100 + Rituximab 375mg/m^2

EXPERIMENTAL

Part 5: G100 at 20, 40, 60, or 80μg/tumor administered IT for up to 6 weeks and rituximab administered as an IV infusion at 375mg/m\^2 on Day 0 and then QW for up to 3 weeks.

Drug: G100; Drug: Rituximab

Interventions

G100 DRUG

GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist

Also known as: glucopyranosyl lipid A stable emulsion, GLA-SE

Part 1: Local Radiation + G100 10μg/tumor; Part 1: Local Radiation + G100 5μg/tumor; Part 2: Local Radiation + G100 10μg/tumor; Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg; Part 2: Local Radiation, G100 20 μg/tumor in Large Tumors; Part 3: Local Radiation + G100 20μg/tumor; Part 4: G100 20μg/tumor and pembrolizumab 200mg; Part 5: G100 + Rituximab 375mg/m^2

Pembrolizumab DRUG

PD-1 Inhibitor

Also known as: Keytruda, MK-3475

Part 2: Local Radiation + G100 10μg/tumor+Pembrolizumab 200mg; Part 4: G100 20μg/tumor and pembrolizumab 200mg

Rituximab DRUG

Rituximab (anti-CD20 antibody)

Part 5: G100 + Rituximab 375mg/m^2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Follicular low-grade NHL:
• In Part 1-3: either treatment naïve (except for France) OR relapsed or refractory following at least one prior treatment.
• In Part 4, enrollment is limited to relapsed OR refractory follicular NHL participants.
• In Part 5, enrollment will include relapsed and refractory CD20+ follicular NHL following at least one but not more than 2 prior treatments.
• Tumor mass(es) accessible for intratumoral injection
• For Part 1-3, are being considered for local radiation therapy and at least one additional site of disease outside the radiation field for assessment of distal (abscopal) response.
• For Part 4 and 5, radiation therapy is omitted. Measurable tumor mass(es) accessible for intratumoral injection must be present for treatment and assessment of response.
• ≥ 18 years of age
• Life expectancy of ≥ 6 months per the investigator
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Electrocardiogram (ECG) without evidence of clinically significant arrhythmia or ischemia
• If female of childbearing potential (FCBP), willing to undergo pregnancy testing and agrees to use two methods of birth control or is considered highly unlikely to conceive during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment
• If male and sexually active with a FCBP, must agree to use highly effective contraception such as latex condom or is sterile (e.g. following a surgical procedure) during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment

You may not qualify if:

• Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics or kinase inhibitors, granulocyte-colony stimulating factor (G-CSF) or granulocyte/monocyte-colony stimulating factor (GM-CSF) within 4 weeks prior to the first scheduled G100 dose
• Investigational therapy within 4 weeks prior to G100 dosing
• Prior administration of other intratumoral immunotherapeutics
• Inadequate organ function including:
• Marrow: Peripheral blood leukocyte count (WBC) \< 3000/mm\^3, absolute neutrophil count ≤ 1500/mm\^3, platelets \< 75000/mm\^3, or hemoglobin \< 10 gm/dL
• Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) \> 2.5 x Upper Limit of Normal (ULN), total serum bilirubin \> 1.5 x ULN (participants with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL)
• Renal: Creatinine \> 1.5x ULN
• Other: INR (international normalized ratio) or partial thromboplastin time (PTT) \>1.5 x ULN
• Significant immunosuppression from:
• Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any dose, or
• Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine or conditions such as common variable hypogammaglobulinemia
• Pregnant or nursing
• Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure
• History of other cancer within 2 years (except non-melanoma cutaneous malignancies and cervical carcinoma in situ)
• Recent (\<1 week ago) clinically significant infection, active tuberculosis or evidence of active hepatitis B, hepatitis C or HIV infection

Sponsors & Collaborators

• Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead
• Merck Sharp & Dohme LLC: collaborator

Related Publications (1)

• Halwani AS, Panizo C, Isufi I, Herrera AF, Okada CY, Cull EH, Kis B, Chaves JM, Bartlett NL, Ai W, de la Cruz-Merino L, Bryan LJ, Houot R, Linton K, Briones J, Chau I, von Keudell GR, Lu H, Yakovich A, Chen M, Meulen Jh T, Yurasov S, Hsu FJ, Flowers CR. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma. Leuk Lymphoma. 2022 Apr;63(4):821-833. doi: 10.1080/10428194.2021.2010057. Epub 2021 Dec 6.

  PMID: 34865586 DERIVED

MeSH Terms

Conditions

Lymphoma, Follicular; Lymphoma, Non-Hodgkin

Interventions

TLR4 agonist G100; pembrolizumab; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was terminated (halted prematurely) for business reasons.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Lisa Knapp

  Clinical Trial Manager

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2015
• First Posted: July 17, 2015
• Study Start: February 3, 2016
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: September 9, 2020
• Results First Posted: September 9, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share