Intratumoral AST-008 Combined With Pembrolizumab or Cemiplimab in Patients With Advanced Solid Tumors
- Written informed consent.
- Male or female ≥18 years of age.
- Must have an advanced inoperable histologically diagnosed solid tumor.
- At least one tumor lesion amenable to repeated IT injection via palpation or ultrasound. Injection of deep visceral lesions is not permitted, except in the optional liver dosing cohort.
- Agrees to provide a newly obtained biopsy of injected and witness lesions (if they can be biopsied based on the investigator's assessment) prior to start of study treatment, and to repeat biopsies twice during study treatment, and to providing the acquired tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously irradiated, but a new or progressing lesion in the radiation field is acceptable.
- In the investigator's opinion the patient may derive clinical benefit from the treatment or is ineligible for a particular form of standard therapy due to tolerability, or the patient failed one or more established standard medical anti-cancer therapies, including:
- In the dose escalation phase and optional liver dosing cohort, exposure to anti-PD-(L)1 or anti-CTLA-4 antibody CPIs is permitted but not required.
- In the Phase 2 MCC expansion cohort: i. At least 4 doses of q2w-administered avelumab or 3 doses of q3w-administered pembrolizumab as the most recent preceding therapy prior to being enrolled in this study with confirmed progression. Pembrolizumab treatment was for recurrent locally advanced or metastatic MCC, or avelumab treatment was for metastatic MCC. Prior anti-CTLA-4 antibody therapy is permitted but not required. ii. Last dose of anti-PD-(L)1 antibody therapy must be within 12 weeks of initiating study treatment. iii. Confirmed progressive disease on anti-PD-(L)1 antibody therapy defined as:
- Treatment duration with the anti-PD-(L)1 antibody was ≥ 8 weeks.
- Documented radiographic progression on two sequential radiographic scans separated by at least 4 weeks per RECIST 1.1. However, if radiographic progression is accompanied with unequivocal clinical progression, then a single scan assessment may be used if, in the opinion of the investigator, the patient is unable to wait 4 weeks for a second scan.
- If progression was only in a lymph node, biopsy confirmation of cancer in the lymph node is required. b. In the Phase 2 CSCC expansion cohort: i. At least 3 doses of q3w-administered cemiplimab as the most recent preceding therapy prior to being enrolled in this study with confirmed progression. Cemiplimab was administered for metastatic CSCC or locally advanced CSCC that was not a candidate for curative surgery or curative radiation. Prior anti-CTLA-4 antibody therapy is permitted but not required. ii. Last dose of cemiplimab therapy must be within 12 weeks of initiating study treatment. iii. Confirmed progressive disease on cemiplimab therapy in the expansion cohorts are defined as:
- Treatment duration with cemiplimab was ≥ 8 weeks.
- Documented radiographic progression on two sequential radiographic scans separated by at least 4 weeks per RECIST 1.1. However, if radiographic progression is accompanied with documented unequivocal clinical progression, then a single scan assessment may be used.
- If progression was only in a lymph node, biopsy confirmation of cancer in the lymph node is required. c. In the optional exploratory expansion cohort(s): i. At least 4 doses of q2w-administered avelumab, or 3 doses of q3w-administered pembrolizumab or cemiplimab, or 2 doses of q4w-administered nivolumab as the most recent preceding therapy prior to being enrolled in this study with confirmed progression. Prior anti-CTLA-4 antibody therapy is permitted but not required. ii. Last dose of anti-PD-(L)1 antibody therapy must be within 12 weeks of initiating study treatment. iii. Confirmed progressive disease on anti-PD-(L)1 antibody therapy defined as:
- Treatment duration with the anti-PD-(L)1 antibody was ≥ 8 weeks.
- Documented radiographic progression on two sequential radiographic scans separated by at least 4 weeks per RECIST 1.1. However, if radiographic progression is accompanied with documented unequivocal clinical progression, then a single scan assessment may be used if, in the opinion of the investigator, the patient is unable to wait 4 weeks for a second scan.
- If progression was only in a lymph node, biopsy confirmation of cancer in the lymph node is required.
- Evaluable disease per RECIST 1.1 with at least two target lesions. Both injectable and non-injectable target lesions should be chosen for efficacy evaluation.
- For the optional exploratory expansion(s) and Phase 2 expansion portions of the study, a maximum of 3 prior lines of systemic treatment for locally advanced or metastatic disease.
- If not menopausal or surgically sterile, willing to practice at least one of the following highly effective methods of birth control for at least a (partner's) menstrual cycle before and for four months after AST-008 and pembrolizumab/cemiplimab administration: (1) Total abstinence from sexual intercourse with a member of the opposite sex; (2) Sexual intercourse with vasectomized male/sterilized female partner; (3) Hormonal female contraceptive (oral, parenteral, or transdermal) for at least 3 consecutive months prior to investigational product administration; (4) Other acceptable forms of birth control (condoms, contraceptive sponge, diaphragm or vaginal ring with spermicide or cream); (5) Use of an intrauterine contraceptive device.
- Full resolution to G0 or baseline of CPI-related adverse effects (including irAEs) and no treatment for these AEs for at least 4 weeks prior to the time of enrollment. See Criterion 11 for more details on severe irAEs. Controlled hypothyroidism is an exception to this criterion.
- For phase 1b escalation phase and optional liver dosing cohort: No history of irAEs from a CPI (defined as any CTCAE G4 or G3 requiring treatment for >4 weeks). For the optional exploratory expansion(s) and phase 2 expansion phase:
- Resolution of CPI-related AEs (including irAEs) back to G0-1 and no corticosteroids for the amelioration of those irAEs for at least 4 weeks prior to first dose of study drug. Controlled hypothyroidism is an exception to this criterion.
- No history of life-threatening irAEs (CTCAE G4) from CPI requiring steroid treatment.
- No history of CTCAE G3 irAEs from CPI requiring steroid treatment (>10 mg/day prednisone or equivalent dose) for >12 weeks.
- Adequate organ function.
- Able and willing to comply with the protocol and the restrictions and assessments therein.
- Small molecule or tyrosine kinase inhibitor within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug, chemotherapy or biological cancer therapy within 3 weeks prior to the first dose of study therapy, nitrosourea, or radioisotope within 6 weeks prior to first dose, or non-recovery to CTCAE G1 or better from the AEs due to cancer therapeutics administered more than 4 weeks earlier.
- Known hypersensitivity to any phosphorothioate oligonucleotide, or previous exposure to a TLR9 agonist drug.
- Previous severe hypersensitivity reaction to treatment with pembrolizumab, cemiplimab or another anti-PD-(L)1 monoclonal antibody.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1.
- Baseline QTc > 480 msec using Fredericia's formula.
- Risk factors for bowel obstruction or bowel perforation (examples include but are not limited to a recent medical history of acute diverticulitis or other infective abdominal condition, or a diagnosis of abdominal carcinomatosis) that could confound interpretation of GI AEs.
- Symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
- Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and are off steroids for at least 14 days prior to first dose of study drug.
- Known history of a hematologic malignancy, malignant primary brain tumor or malignant sarcoma, or of another malignant primary solid tumor (other than that under study), unless the patient has undergone potentially curative therapy with no evidence of that disease for 3 years. Note: The time requirement for no evidence of disease for 3 years does not apply to the tumor for which a patient is enrolled in the study. The time requirement also does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
- History of pneumonitis or interstitial lung disease or evidence of such as determined by HRCT at baseline.
- Known infection with HIV-1, HIV-2, hepatitis B (surface antigen), or hepatitis C. Baseline testing is not required for patient enrollment.
- Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo or resolved childhood asthma/atopy are exceptions to this rule. Patients requiring intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism that is stable on hormone replacement will not be excluded from the study.
- Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15 days or other immunosuppressive drugs within 30 days prior to start of the study. Inhaled and topical corticosteroids are permitted. Up to 10 mg/day prednisone or equivalent is permitted as replacement therapy for adrenal insufficiency only.
- Active infection requiring therapy.
- Any thromboembolic event within the last 6 months or anticoagulation with therapeutic (non-prophylactic) intent.
- Patients who have received prior thoracic radiation with a dose >30 Gy within 26 weeks of the first dose of study drug.
- Received an investigational product or been treated with an investigational device within 30 days prior to first drug administration or will start any other investigational product or device study within 30 days after last study drug administration.
- History or clinical evidence of any surgical or medical condition which the investigator judges as likely to interfere with the results of the study or pose an additional risk in participating e.g., rapidly progressive or uncontrolled disease involving a major organ system—vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine or an immunodeficiency, or clinically significant active psychiatric or abuse disorders.
- At the time of signing informed consent is a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
- Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
This study will be conducted in 2 phases. Phase 1 evaluates AST-008 given in combination with pembrolizumab in patients with advanced solid tumors in a classical 3+3 dose escalation design, with up to five ascending dose cohorts of AST-008 and enrollment of 3 patients per cohort to identify an RP2D. Patients will be dosed twice with AST-008 as a monotherapy before adding pembrolizumab, which will be added starting at the second cycle. Once the MTD or highest escalation cohort has been reached, or notable efficacy has been observed at a given dose level, and a decision as to a RP2D has been made, a two two-stage expansion cohorts will be initiated. Phase 2 will evaluate the RP2D of AST-008 given in combination with pembrolizumab or cemiplimab in two expansion cohorts following a modified Simon 2-stage optimal design comprised of patients with Merkel cell carcinoma (MCC) or cutaneous squamous cell carcinoma (CSCC). who previously received and have progressed on an anti-PD-(L)1 CPI or are otherwise refractory to CPI therapy. Patients in the MCC cohort will receive IT AST-008 combined with a fixed, standard dose of pembrolizumab while the CSCC cohort will receive IT AST-008 combined with a fixed, standard dose of cemiplimab.
Trial Phase Phase I/II
Trial Type Treatment
- Primary ID AST-008-102
- Secondary IDs NCI-2019-01227
- Clinicaltrials.gov ID NCT03684785