Intervention: Caffeine, 8-((3-methoxypropyl)amino)-
Trial phase: Phase 1 | Phase 2
SMILES: COCCCNc1nc2c(c(=O)n(C)c(=O)n2C)n1C
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 4
Group description: 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.
Eligibility criteria:
Inclusion Criteria:

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

Exclusion Criteria:

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
Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease.
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
Psychiatric, other medical illness or other condition that in the opinion of the principal investigator (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 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

Use of anti-coagulant agents or history a significant bleeding diathesis. (If a superficial lymph node or subcutaneous mass is to be injected, participants 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 participants enrolled in Part 2 or Part 4 with the potential to receive pembrolizumab:

History of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease
Received a live virus vaccine within 30 days of planned study start
Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft vs. 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 participant 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.