A strategic restructuring including the planned conclusion of clinical oncology development programs and no further sponsoring of the development of SD-101.

This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, biologic activity, and preliminary efficacy of intratumoral SD-101 injections in combination with intravenous pembrolizumab in patients with metastatic melanoma or recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).

This study will be conducted in 2 phases. Phase 1 evaluates SD-101 given in combination with pembrolizumab in melanoma populations (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease) in up to 4 Dose Escalation cohorts to identify a recommended Phase 2 dose (RP2D) to be evaluated in up to 4 Dose Expansion cohorts in Phase 2. Phase 2 also includes up to 4 Dose Expansion cohorts of patients with HNSCC (anti-PD-1/L1 naïve and anti-PD-1/L1 experienced with progressive disease).

[Inclusion Criteria (Phase 1 and Phase 2)]

1. Willing and able to provide written informed consent for the trial

2. Aged 18 years and older

3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1

4. Patient must have adequate organ function as indicated by the following laboratory values:

   1. Hematological:

      • Absolute neutrophil count (ANC) ≥ 1,500 /mcL
      • Platelet count ≥ 100,000 /mcL
      • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

   2. Renal:

      • Serum creatinine ≤ 1.5 × upper limit of normal (ULN) OR
      • Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60 mL/min for subject with creatinine levels > 1.5 × institutional ULN

   3. Hepatic:

      • Serum total bilirubin:
      • ≤ 1.5 × ULN OR
      • < 3 × ULN for persons with Gilbert's syndrome OR
      • Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 × ULN
      • Aspartate transaminase (AST) and alanine transaminase (ALT) (also known as serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase)
      • ≤ 2.5 × ULN OR
      • ≤ 5 × ULN for patients with liver metastases

   4. Coagulation:

      • International normalized ratio or prothrombin time (PT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy, and as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
      • Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy, and as long as PT or PTT is within therapeutic range of intended use of anticoagulants

5. Have provided 2 tissue biopsy samples taken of the target lesion (Lesion A) as a single biopsy split into 2 samples or 2 separate biopsies that meet the minimal sample size requirement per the study laboratory manual. One sample is for determining PD-L1 expression level by immunohistochemistry and can be an archival sample of the anticipated target lesion that has been collected within 3 months of screening. The other sample is for RNA expression profiling and must be a fresh biopsy.

6. Life expectancy of at least 6 months

7. Female patients of childbearing potential, as defined in Section 5.2.1, must have a negative urine or serum pregnancy test within 72 hours prior to taking the first dose of trial treatment. If the urine test is positive or cannot be confirmed as negative then a serum test is required which must be negative for the patient to enroll. Women of childbearing potential (WOCBP) must be willing to use 2 medically acceptable methods of contraceptive from Day 1 through 120 days after the last dose of trial treatment. The 2 medically acceptable birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or guidelines. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents).

   Male patients of reproductive potential, as described in Section 5.2.1, must agree to use an adequate method of contraception from Day 1 through 120 days after the last dose of trial treatment.

   Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

   [Inclusion Criteria (Phase 1 only: Melanoma)]

8. Histologically or cytologically confirmed unresectable or metastatic (stage IV) melanoma

9. For Phase 1 Escalation Cohorts 1-4, must have at least 1 lesion that qualifies as a target lesion per RECIST v1.1 except for the minimum measurement of 10 mm in diameter for superficial lesions, is easily accessible (palpable or can be visualized by ultrasound), and is amenable to multiple intratumoral injections. If superficial, the target lesion must be documented photographically.

   [Inclusion Criteria (Phase 2 only: Melanoma)]

10. Histologically or cytologically confirmed recurrent or unresectable or metastatic (stage IV) melanoma

11. Must have at least 2 lesions that qualify as a target lesion per RECIST v1.1, and 1 of the qualifying lesions must be easily accessible (palpable or can be visualized by ultrasound) and amenable to multiple intratumoral injections. The target lesion should be of sufficient size such that the required tumor biopsies do not significantly affect tumor assessment per RECIST v1.1. If superficial, the target lesion must measure at least 10 mm in diameter, be measured by calipers, and be documented photographically. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Approval from the Medical Monitor is required to inject a previously radiated lesion.

12. Expansion Cohort 2: Must have documented PD per RECIST v1.1 on a prior treatment regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition of PD per RECIST v1.1)

13. Expansion Cohort 8: Must have all of the following:

    1. Received at least 2 doses of an anti-PD-1/L1 therapy
    2. PD occurred within 3 months after last dose of anti-PD-1/L1 therapy
    3. Documented PD per RECIST v.1.1, which has been confirmed by a second assessment at least 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression

    [Inclusion Criteria (Phase 2 only: HNSCC)]

14. Histologically or cytologically confirmed recurrent or metastatic HNSCC that could not be treated with curative intent

15. Must have at least 1 lesion that qualifies as a target lesion per RECIST v1.1, and which must be easily accessible (palpable or can be visualized by ultrasound) and amenable to multiple intratumoral injections. The target lesion should be of sufficient size such that the required tumor biopsies do not significantly affect tumor assessment per RECIST v1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Approval from the Medical Monitor is required to inject a previously radiated lesion.

16. Expansion Cohort 4: Must have documented confirmed PD per RECIST v1.1 on a prior treatment regimen containing an anti-PD-1/L1 drug (see Appendix 6 for definition of PD per RECIST v1.1)

17. Expansion Cohort 7: Must have all of the following:

    1. Received at least 2 doses of an anti-PD-1/L1 therapy, where the last dose of anti-PD-1/L1 therapy was within 6 months of study enrollment (Day 1)
    2. Refractory response, ie, PD occurred within 3 months duration of the start of treatment on anti-PD-1/L1 therapy; OR resistant response, ie, PD occurred beyond 3 months duration of treatment on anti-PD-1/L1 therapy and within 6 months after the last dose of treatment on anti-PD-1/L1 therapy
    3. Documented PD per RECIST v.1.1, which has been confirmed by a second assessment at least 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression

[Exclusion Criteria (Phase 1 and Phase 2)]

1. Received systemic chemotherapy or biological cancer therapy (except anti-PD-1/L1 therapy) within 3 weeks prior to study enrollment

2. Received prior radiotherapy within 2 weeks of start of study therapy. A shorter washout period may be permitted after approval by the Medical Monitor.

3. Received small molecule inhibitor targeted therapy, such as tyrosine kinase inhibitors, within 2 weeks prior to study enrollment

4. Has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics prior to study enrollment

   NOTE: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia or Grade 2 AEs that qualify as Grade 2 due to replacement hormonal or steroid therapy are exceptions to this criterion and may qualify for the study with approval by a Dynavax Medical Monitor.

   If a patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to enrollment.

5. Received a transfusion of blood products (including platelets or red blood cells) or colony-stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to study enrollment

6. Is expected to require any other form of anti-cancer therapy while in the trial

7. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy (including immune modulators or systemic corticosteroids) within 7 days prior to study enrollment

8. Positive for active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection as determined by laboratory tests for HBsAg, anti-HBc, and anti-HBs; anti-HCV; and anti-HIV -1/2, respectively

9. History of or current uveal or ocular or mucosal melanoma

10. Active infection including cytomegalovirus

11. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 120 days after the last dose of trial treatment

12. Active autoimmune disease requiring systemic treatment in the past 2 years or a disease that requires immunosuppressive medication including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, or autoimmune thrombocytopenia. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

13. Current pneumonitis or history of (non-infectious) pneumonitis that required steroids

14. An immune-related AE from a previous immunotherapeutic agent that has not resolved to Grade 1 or less prior to study enrollment. The exception is a Grade 2 AE which qualifies as Grade 2 due to replacement steroid therapy which may be allowed with approval by a Dynavax Medical Monitor.

15. Known active central nervous system metastases or carcinomatous meningitis

    NOTE: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of trial treatment and with any neurologic symptoms returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

16. Use of any investigational agent within the last 28 days prior to study enrollment

17. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.

18. Any other significant medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with trial participation or trial drug administration that may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for this trial

19. History of sensitivity to any component of SD-101 or hypersensitivity reaction to treatment with a monoclonal antibody and/or any of its excipients

20. Any known additional malignancy that is progressing or requires active treatment. Exceptions are cutaneous melanoma or HNSCC under study per protocol, or basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer that has undergone potentially curative therapy.

    [Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 1 and 5 only)]

21. Melanoma considered resectable with curative intent

22. Prior therapy with an anti-PD-1/L1 agent

23. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients

    [Exclusion Criteria (Phase 2, Melanoma Expansion Cohorts 2 and 8 only)]

24. Melanoma considered resectable with curative intent

25. Any prior combination therapy involving agents given by intratumoral injection that target the innate immune pathway or system such as oncolytic viral or microbial therapy (eg, T-VEC [talimogene laherparepvec]), toll-like receptors (TLR) agonists, STING or RIG-1 and an anti-PD-1/L1 inhibitor

    [Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 3 and 6 only)]

26. HNSCC considered resectable with curative intent

27. Prior therapy with an anti-PD-1/L1 agent

28. Require anticoagulation therapy

    [Exclusion Criteria (Phase 2, HNSCC Expansion Cohorts 4 and 7 only)]

29. HNSCC considered resectable with curative intent

30. Any prior combination therapy involving agents given by intratumoral injection that target the innate immune pathway or system such as oncolytic viral or microbial therapy (eg, T-VEC), TLR agonists, STING or RIG-1 and an anti-PD-1/L1 inhibitor

31. Require treatment on anticoagulation therapy

Data will be shared under guidance of the New Rule - FDAAA 801 eff. Jan 2017. 3/2017 - additional changes forthcoming.