Clinical trial NCT02521870: A Trial of Intratumoral Injections of SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Official title: A Phase 1b/2, Open-label, Multicenter, Dose-escalation and Expansion Trial of Intratumoral SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (SYNERGY-001)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Metastatic Melanoma
Head Neck Cancer
Keywords: Skin Cancer
Skin Tumors
Head and Neck Squamous Cell Carcinoma
Cancer Immunotherapy
Lead sponsor: Dynavax Technologies Corporation
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-08-13
Enrollment: 241
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: \[Inclusion Criteria (Phase 1 and Phase 2)\]

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

Primary outcomes:
measure: Phase 1 Dose Escalation Only - Number of Participants With DLTs
timeFrame: Day 1 through Day 29
measure: Phase 1 Dose Escalation and Phase 2 Dose Expansion - Overall Response Rate (ORR) by Analysis Group
timeFrame: Day 1 through Day 743
Secondary outcomes:
measure: Phase 1 Dose Escalation and Phase 2 Dose Expansion - Time to Objective Response by Analysis Group
timeFrame: Day 1 through Day 743
measure: Phase 1 Dose Escalation and Phase 2 Dose Expansion - Duration of Response by Analysis Group
timeFrame: Day 1 through Day 743
measure: Phase 1 Dose Escalation and Phase 2 Dose Expansion - Disease Control Rate (DCR) by Analysis Group
timeFrame: Day 1 through Day 743
measure: Phase 1 Dose Escalation and Phase 2 Dose Expansion - Progression-Free Survival Rate by Analysis Group
timeFrame: Day 1 through Day 743
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama School of Medicine
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford Hospitals and Clinics
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Georgia Cancer Center - Northside Hospital Central Research Department
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Healthcare
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Cancer Center
state: Minnesota
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Morristown
country: United States
facility: Atlantic Health
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center - Seidman Cancer center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Care - Huntsman Cancer institute
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Tweed Heads
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Wollstonecraft
country: Australia
facility: Melanoma Institute
state: New South Wales
city: Kurralta Park
country: Australia
facility: Adelaide Cancer Centre - Ashford Cancer Centre
state: South Australia
city: Nedlands
country: Australia
facility: Hollywood Private Hospital / Affinity Research
state: Western Australia
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Buxtehude
country: Germany
facility: Klinikum BuxtehudeDermato-Onkologie Studienzentrale
city: Dresden
country: Germany
facility: Uniklinikum Dresden Klinik und Poliklinik für Dermatologie
city: Frankfurt
country: Germany
facility: Universitätshautklinik Frankfurt
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Jena
country: Germany
facility: HNO-Universitätsklinik Jena
city: Magdeburg
country: Germany
facility: Universitätshautklinik Magdeburg
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Tubingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
Study officials:
affiliation: UCLA School of Medicine (Melanoma)
name: Antoni Ribas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCSD Moores Cancer Center (HNSCC)
name: Ezra Cohen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Magdeburg
name: Thomas Tüting, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ribas A, Medina T, Kummar S, Amin A, Kalbasi A, Drabick JJ, Barve M, Daniels GA, Wong DJ, Schmidt EV, Candia AF, Coffman RL, Leung ACF, Janssen RS. SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. Cancer Discov. 2018 Oct;8(10):1250-1257. doi: 10.1158/2159-8290.CD-18-0280. Epub 2018 Aug 28.