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Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma

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ClinicalTrials.gov Identifier: NCT02501473
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : October 19, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Immune Design

Brief Summary:
This is a Phase 1/2 open label trial of G100 in patients 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 following 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 clinical efficacy of G100 will be examined alone or with pembrolizumab or rituximab.

Condition or disease Intervention/treatment Phase
Follicular Low Grade Non-Hodgkin's Lymphoma Drug: G100 Drug: Pembrolizumab Drug: Rituximab Phase 1 Phase 2

Detailed Description:

This is a multi-center Phase 1/2 open label trial of intratumoral G100 in patients with low grade NHL. Patients with NHL will be enrolled and receive G100 to an accessable tumor mass. Clinical response will be evaluated in the injected lesion and systemic (abscopal) responses will be evaluated in distal areas involved with tumor.

The study will be conducted in 5 parts. In Part 1, Dose Escalation, 2 sequentially enrolled cohorts of patients will be treated at one of 2 dose levels of G100 using a standard escalation design. In this portion of the study, both follicular and marginal zone NHL will eligible. In Part 2, 2 groups of patients with follicular NHL may be examined. One group will be randomly assigned to receive either single agent G100 intratumorally at the maximum safe dose determined in Part 1 following local radiation or will receive the same treatment regimen sequentially administered with pembrolizumab. A second treatment group may be explored if the safety profile in Part 1 is acceptable. In this optional group, patients with injectable tumors of 4 cm or greater would be enrolled and treated with a higher dose of G100. In Part 3, expansion of a higher dose (20µg of G100) in patients with follicular NHL will be enrolled to receive local radiation therapy and intratumoral G100 (no tumor size requirement in this arm). In Part 4, Dose Escalation and Expansion, a dose of 20µg of G100 will be examined as a treatment of 1 or more tumor lesions (up to 4) with pembrolizumab in order to establish safety and examine clinical and biomarker responses in patients receiving increasing total systemic doses of G100. In Part 5, Dose Escalation, increasing doses of G100 (in combination with rituximab) in a single tumor lesion will be examined. Once the highest dose has been established as safe, a Patient Expansion group may be treated.

The primary goal of this study is to determine the safety and tolerability of different doses of G100 when administered by intratumoral injection. The development of anti-tumor immune responses and preliminary evidence of clinical responses in local and distal tumor sites will also be examined.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 117 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma
Actual Study Start Date : June 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : March 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Part 1: Dose Escalation Cohort 1
Intratumoral injections of G100 at 5μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 1: Dose Escalation Cohort 2
or Intratumoral injections of G100 at 10μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 2: Patient Expansion G100 and Pembrolizumab
Intratumoral injections G100 or sequential intratumoral G100 and pembrolizumab
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Drug: Pembrolizumab
PD-1 Inhibitor
Other Name: Keytruda

Experimental: Part 2: Large Tumor (Optional)
Intratumoral injections G100 at 20 μg
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 3: Expansion of Dose Group
Intratumoral G100 at 20 µg/dose in patients without restriction of tumor size
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Experimental: Part 4: G100 Escalation and Expansion with pembrolizumab
Dose Escalation: Cohort 1: G100 20 μg (GLA component)/ lesion in 1 tumor Cohort 2: G100 20 μg/lesion in 2 tumor lesions (40 μg total) Cohort 3: G100 20 μg/lesion in 3 tumor lesions (60 μg total) Cohort 4: G100 20 μg/lesion in 4 tumor lesions (80 μg total). Patient Expansion at each dose level will be allowed after each cohort has been deemed safe.
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Drug: Pembrolizumab
PD-1 Inhibitor
Other Name: Keytruda

Experimental: Part 5: Dose Escalation and Expansion with rituximab
Dose escalation of Intratumoral G100 into a single lesion. Cohort 1: G100 20 µg (GLA component) in single tumor lesion Cohort 2: G100 40 µg in a single tumor lesion Cohort 3: G100 60 µg in a single tumor lesion Cohort 4: G100 80 µg in a single tumor lesion Once a MTD has been establish an expansion of that cohort will occur
Drug: G100
GLA is a fully synthetic toll-like receptor-4 (TLR4) agonist
Other Name: glucopyranosyl lipid A stable emulsion, GLA-SE

Drug: Rituximab
CD20
Other Names:
  • Rituxan
  • MabThera




Primary Outcome Measures :
  1. Safety and Tolerability by assessing the frequency and severity of adverse events [ Time Frame: Up to 2 years ]
    To evaluate the safety and tolerability of ascending doses of intratumoral G100 in patients with follicular NHL receiving local radiation by assessing the frequency and severity of adverse events


Secondary Outcome Measures :
  1. Clinical Response Assessment as a preliminary indication of efficacy [ Time Frame: Day 1 to Progression (estimated 24 + months) ]
    Assess clinical responses at local and distal sites of disease as a preliminary indication of efficacy

  2. Abscopal tumor response in non-treated, distal tumor sites [ Time Frame: Screening to End of Study Visit (expected average is 24 Months) ]
    To assess abscopal tumor responses in non-treated, distal tumor sites

  3. Exploratory Biomarkers of immunologic and tumor response [ Time Frame: Screening to End of Study Visit (expected average is 24 Months) ]
    Assess blood and tumor samples for exploratory biomarkers of immunologic and tumor response



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Follicular low-grade NHL: 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 patients.
    • In Part 5, enrollment during Dose Escalation will include CD20+ follicular NHL either treatment naïve or relapsed or refractory following at least one prior treatment. During Patient Expansion, enrollment will be limited to relapsed or refractory follicular NHL.
  2. Tumor mass(es) accessible for intratumoral injection and 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 Parts 4 and 5, radiation therapy is omitted. Measurable tumor mass(es) accessible for intratumoral injection must be present for treatment and assessment of response.

  3. ≥ 18 years of age
  4. Life expectancy of ≥ 6 months per the investigator
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  6. ECG without evidence of clinically significant arrhythmia or ischemia
  7. 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
  8. 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

Exclusion Criteria:

  1. Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics or kinase inhibitors, G-CSF or GM-CSF within 4 weeks prior to the first scheduled G100 dose
  2. Investigational therapy within 4 weeks prior to G100 dosing
  3. Prior administration of other intratumoral immunotherapeutics
  4. Inadequate organ function including:

    1. Marrow: Peripheral blood leukocyte count (WBC) < 3000/mm3, absolute neutrophil count ≤ 1500/mm3, platelets < 75000/mm3, or hemoglobin < 10 gm/dL
    2. Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) > 2.5 x Upper Limit of Normal (ULN), total serum bilirubin > 1.5 x ULN (patients with Gilbert's Disease may be included if their total bilirubin is ≤3.0 mg/dL)
    3. Renal: Creatinine > 1.5x ULN
    4. Other: INR (prothrombin time ratio) or partial thromboplastin time (PTT) >1.5 x ULN
  5. Significant immunosuppression from:

    1. Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any dose, or
    2. Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine or conditions such as common variable hypogammaglobulinemia
  6. Pregnant or nursing
  7. Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure
  8. History of other cancer within 2 years (except non-melanoma cutaneous malignancies and cervical carcinoma in situ)
  9. Recent (< 1 week ago) clinically significant infection, active tuberculosis or evidence of active hepatitis B, hepatitis C or HIV infection
  10. Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease.
  11. Significant autoimmune disease, including active non-infectious pneumonitis, with the exception of alopecia, vitiligo, hypothyroidism or other conditions that have never been clinically active or were transient and have completely resolved and require no ongoing therapy
  12. Psychiatric, other medical illness or other condition that in the opinion of the PI prevents compliance with study procedures or ability to provide valid informed consent
  13. History of significant adverse or allergic reaction to any component of G100 and, if enrolled in Part 2 or Part 4, pembrolizumab and/or any of its excipients, and if enrolled in Part 5, anti-CD20 antibodies including rituximab and/or any of its excipients
  14. Use of anti-coagulant agents or history a significant bleeding diathesis. (If a superficial lymph node or subcutaneous mass is to be injected, patients on agents such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or clopidogrel are eligible and these agents do not have to be withheld. For procedures with moderate or significant risk of bleeding, long-acting agents such as aspirin or clopidogrel should be discussed with the Medical Monitor and may need to be discontinued before G100 therapy.

    For patients enrolled in Part 2 or Part 4 with the potential to receive pembrolizumab:

  15. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease
  16. Received a live virus vaccine within 30 days of planned study start
  17. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of GVHD.)
  18. Has had an allogeneic tissue/solid organ transplant
  19. Has received prior therapy with an anti-PD-1, anti-programmed death ligand (PD-L)1, or anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical trials or was previously treated with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02501473


Contacts
Contact: Immune Design 650-392-8312 clinicaltrials@immunedesign.com

Locations
United States, California
City of Hope Active, not recruiting
Duarte, California, United States, 91010
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Erika Cavallone    415-476-4765    erika.cavallone@ucsf.edu   
Contact: Jeffrey Marsal    1 (415) 353-2145    jeffrey.marsal@ucsf.edu   
United States, Connecticut
Yale Comprehensive Cancer Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Laura Leary    203-737-8884    laura.leary@yale.edu   
Contact: Kylie Boyhen    1 (203) 737-8897    kylie.boyhen@yale.edu   
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Malesa Pereira    813-745-4090    malesa.pereira@moffitt.org   
Contact: Jennifer Gemmer    1 (813) 745-3861    jennifer.gemmer@moffitt.org   
United States, Georgia
Winship Cancer Institute of Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Amanda Hutchison-Rzepka    404-778-3935    ahutch7@emory.edu   
Contact: Ashley Archer    1 (404) 778-8641    asarche@emory.edu   
Georgia Cancer Center at Augusta University Recruiting
Augusta, Georgia, United States, 30912
Contact: Lisa Marshall    706-721-5095    lmarshall@augusta.edu   
Contact: Sandra Wall    1 (706) 721-4430    swall@augusta.edu   
United States, Missouri
Washington University Active, not recruiting
Saint Louis, Missouri, United States, 63130
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Elizabeth Franks    503-494-9324    frankse@ohsu.edu   
Contact: Bethany Wollam    1 (503) 494-4704    wollamb@ohsu.edu   
United States, South Carolina
Greenville Health System Recruiting
Greenville, South Carolina, United States, 29605
Contact: Lisa Johnson, RN    864-455-3600    ljohnson4@ghs.org   
Contact: Jill Cantrell, RN    864-455-3600    jcantrell@ghs.org   
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Karen Pena, CCRP    801-213-4233    karen.pena@hci.utah.edu   
Contact: Brandon Smiley    1 (801) 587-4769    brandon.smiley@hci.utah.edu   
United States, Washington
Northwest Medical Specialties Recruiting
Tacoma, Washington, United States, 98405
Contact: Debi Kadoun    253-428-8752    dkadoun@nwmsonline.com   
Contact: Nicole Reinsch    1 (253) 200-3147    nreinsch@nwmsonline.com   
France
CHU de Rennes - Hopital Pontchailou Recruiting
Rennes, Bretagne, France, 35033
Contact: Sophie Rochas, MD    +33299289810    sophie.rochas@chu-rennes.fr   
Contact: Nolwenn Boissel    +33299289201      
Spain
Clinica Universitaria de Navarra Recruiting
Pamplona, Navarra, Spain, 31008
Contact: Usua Montes    +34948255400    umontes@unav.es   
Contact: Nicolas Martinez Calle, MD    +34948296397    nmartinezc@unav.es   
Hospital Santa Creu i Sant Pau Recruiting
Barcelona, Spain, 08025
Contact: Jessica de Rueda    +34935537120    mderueda@santpau.cat   
Contact: Silvia Borrell    +34935537142    sborrell@santpau.cat   
Hospital Universitario Virgen Macarena Recruiting
Sevilla, Spain, 41009
Contact: Isabel Araujo    +34955926578    isabelaraujo.oncomacarena@gmail.com   
Contact: Esteban Nogales Fernandez, MD    +34955008932    esteban.nogales@gmail.com   
United Kingdom
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom, M20 4BX
Contact: Clare Day, MD    +01619187516    clare.day@christie.nhs.uk   
Contact: Joanna Dash, MD    +4401619187226    joanna.dash@christie.nhs.uk   
Royal Marsden Hospital Recruiting
Sutton, United Kingdom, SM2 5PT
Contact: Sheila Azouji-Benjamin    +4402086613729    sheila.azouji-benjamin@rmh.nhs.uk   
Contact: Julie Duncan    +442086426011    julie.duncan@rmh.nhs.uk   
Sponsors and Collaborators
Immune Design
Merck Sharp & Dohme Corp.
Investigators
Study Director: Lisa Knapp Clinical Trial Manager

Responsible Party: Immune Design
ClinicalTrials.gov Identifier: NCT02501473     History of Changes
Other Study ID Numbers: IMDZ-G142
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Immune Design:
follicular lymphoma
FL
low-grade lymphoma
Non-Hodgkin's Lymphoma
follicular NHL
Marginal Zone

Additional relevant MeSH terms:
Immune System Diseases
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Pembrolizumab
Rituximab
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents