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

Conditions:Lymphoma, Lymphoma
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:June 2015
End Date:March 2021
Contact:Immune Design

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Phase 1/2 Study of Intratumoral G100 With Or Without Pembrolizumab or Rituximab In Patients With Follicular Non-Hodgkin's Lymphoma

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.

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.

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

- 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

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

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

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
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