This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety,
tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral
AST-008 injections alone and in combination with intravenous pembrolizumab in patients with
advanced solid tumors.
Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate
dose levels of AST-008 given with a fixed dose of pembrolizumab.
Phase 2 is an expansion cohort to further evaluate AST-008 given in combination with
pembrolizumab in a specific population to provide a preliminary estimate of efficacy in
patients who have previously received and not responded to anti-PD-1 or anti-PD-L1 antibody
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-stage expansion cohort will be
Phase 2 will evaluate the RP2D of AST-008 given in combination with pembrolizumab in an
expansion cohort following a modified Simon 2-stage optimal design comprised of patients with
a specific indication who previously received and did not responded anti-PD-1 or anti-PD-L1
1. Written informed consent.
2. Male or female ≥18 years of age.
3. Must have an advanced inoperable histologically diagnosed solid tumor.
4. At least one tumor lesion amenable to repeated IT injection via palpation or
ultrasound. Injection of deep visceral lesions is not permitted.
5. 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.
6. In the investigator's opinion the patient may derive clinical benefit from the
treatment or is ineligible for a particular form of standard therapy on medical
grounds, or the patient failed or did not tolerate one or more established standard
medical anti-cancer therapies, including:
1. In the dose escalation phase, exposure to anti-PD-(L)1 or anti-CTLA-4 antibody
CPIs is permitted but not required.
2. In the dose expansion phase, stable or progressive disease after 12 weeks of
therapy with an anti-PD(L)1 antibody. Prior anti-CTLA-4 antibody therapy is
permitted but not required.
7. For expansion cohorts only: lack of response on/after the most recent treatment
8. 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.
9. For the expansion portion of the study, a maximum of 3 prior lines of systemic
treatment for locally advanced or metastatic disease.
10. 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
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.
11. 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 12 for more details on severe irAEs.
12. For phase 1b escalation phase: No history of irAEs from a CPI (defined as any CTCAE G4
or G3 requiring treatment for >4 weeks).
For phase 2 expansion phase:
1. Resolution of CPI-related AEs (including irAEs) back to G0-1 and no
corticosteroids for the amelioration of those irAEs for at least four weeks prior
to first dose of study drug.
2. No history of life-threatening irAEs (CTCAE G4) from CPI requiring steroid
3. No history of CTCAE G3 irAEs from CPI requiring steroid treatment (>10 mg/day
prednisone or equivalent dose) for >12 weeks.
13. Adequate organ function.
14. Able and willing to comply with the protocol and the restrictions and assessments
1. 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, nitrosurea, 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.
2. Known hypersensitivity to any phosphorothioate oligonucleotide, or previous exposure
to a TLR9 agonist drug.
3. Previous severe hypersensitivity reaction to treatment with pembrolizumab or another
anti-PD(L)1 monoclonal antibody.
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1.
5. Baseline QTc > 480 msec using Fredericia's formula.
6. 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.
7. Symptomatic ascites or pleural effusion. A patient who is clinically stable following
treatment for these conditions (including therapeutic thoraco- or paracentesis) is
8. 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
9. 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.
10. History of pneumonitis or interstitial lung disease or evidence of such as determined
by HRCT at baseline.
11. Known infection with HIV-1, HIV-2, hepatitis B (surface antigen), or hepatitis C.
Baseline testing is not required for patient enrollment.
12. 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.
13. 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.
14. Active infection requiring therapy.
15. Therapeutic anticoagulation, meaning any thromboembolic event within the last 12
months or anticoagulation with therapeutic (non-prophylactic) intent.
16. Patients who have received prior thoracic radiation with a dose >30 Gy within 26 weeks
of the first dose of study drug.
17. 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
18. 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.
19. 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).
20. Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study.