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

Inclusion Criteria:

• Follicular low-grade NHL (grades 1, 2, 3A):

• In Parts 1-3, either treatment naive or relapsed or refractory following at least one prior treatment. For France, patients with either relapsed or refractory only. In Part 1 Dose Escalation only, in addition to follicular NHL, marginal zone B cell lymphomas: either treatment naive or relapsed or refractory following at least one prior treatment.

• In Part 4, enrollment is limited to relapsed or refractory follicular NHL patients who have received at least 3 prior systemic treatments, one of which was or included an anti-CD20 antibody.

• In Part 5, enrollment will include relapsed or refractory CD20+ follicular NHL following at least one but not more than 2 prior treatments.

• Tumor mass(es) accessible for intratumoral injection. Imaging assisted injections are allowed.

• For Parts 4 and 5, 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

• 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 or if receiving rituximab, 12 months after last treatment

• If male and sexually active with a FCBP, must agree to use 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 or if receiving rituximab, 12 months after last treatment

Exclusion Criteria**

• Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics or kinase inhibitors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage 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 G100 or other intratumoral immunotherapeutics
• Inadequate organ function including:
• Marrow: Peripheral blood leukocyte count (WBC) <3000/mm3, absolute neutrophil count ≤1500/mm3, platelets <75000/mm3, or hemoglobin <10 gm/dL
• Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) >2.5 × the upper limit of normal (ULN), total serum bilirubin >1.5 × ULN (patients with Gilbert's Disease may be included if their total bilirubin is 3.0 mg/dL)
• Renal: Creatinine >1.5 × ULN
• Other: international normalized ratio (INR) or partial thromboplastin time (PTT) >1.5 × 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 hypogamma¬globulinemia
• 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 human immunodeficiency virus (HIV) infection
• Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease. In Parts 4 and 5, any involvement with lymphoma in a closed or confined space such as the retroorbital area will need to be pre-approved by the Medical Monitor.
• 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. (Replacement therapy for hypothyroidism or diabetes is allowed.)
• 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
• History of significant adverse or allergic reaction to any component of G100, and if enrolled in 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
• Use of anti-coagulant agents or history a significant bleeding diathesis.
• Has received a live vaccine within 30 days prior to the first dose of study drug (Applies to patients who may receive either pembrolizumab or rituximab). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

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

• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease
• 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 graft versus host disease [GVHD].)
• Has had an allogeneic tissue/solid organ transplant
• 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.