A Phase 1b/2 Study of Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Advanced Solid Tumors
Objective
This is a phase 1b/2, open-label, two-part, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab or cemiplimab in patients with advanced solid tumors.
Study Arms
- Experimental: Dose Escalation Phase 1b
- Experimental: Dose Expansion Phase 2; Merkel cell carcinoma
- Experimental: Dose Expansion Phase 2, cutaneous squamous cell carcinoma
- Experimental: Exploratory Phase 2, Merkel cell carcinoma, melanoma
Eligibility
1. Written informed consent.
2. Male or female ≥18 years of age.
3. Must have an advanced inoperable histologically diagnosed solid tumor.
- Phase 2 MCC Expansion Cohort: locally advanced or metastatic Merkel cell caricinoma
- Phase 2 CSCC Expansion Cohort: locally advanced or metastatic cutaneous squamous cell carcinoma
- Phase 2 Exploratory Expansion Cohort: locally advanced or metastatic Merkel cell carcinoma or advanced or metastatic melanoma
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 two lesions: a lesion to be injected and an uninjected (witness) lesion (if they can be biopsied based on the Investigator's assessment) prior to the first dose of cavrotolimod, and to repeat biopsies of these two lesions twice during study treatment, and to providing the acquired tissue for biomarker analysis.
6. Phase 1b:
- 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. Exposure to anti-PD-(L)1 or anti-CTLA-4 antibody CPIs is permitted but not required.
Phase 2 MCC Expansion Cohort:
- At least a minimum number of cycles of avelumab or pembrolizumab. Prior anti-CTLA-4 antibody therapy, including as most recent preceding therapy in combination with avelumab or pembrolizumab, is permitted but not required.
- Confirmed progressive disease during treatment with avelumab or pembrolizumab therapy,
Phase 2 CSCC Expansion Cohort
- At least a minimum number of cycles of cemiplimab or pembrolizumab. Prior anti-CTLA-4 antibody therapy, including as most recent preceding therapy in combination with cemiplimab or pembrolizumab, is permitted but not required.
- Confirmed progressive disease on cemiplimab or pembrolizumab therapy
Phase 2 Exploratory Expansion Cohort(s):
- Treatment duration with anti-PD-(L)1 antibody ≥8 weeks as the most recent preceding therapy prior to being enrolled in this study with confirmed progression. Anti-PD-(L)1 was administrated for metastatic or locally advanced MCC or melanoma. Prior anti-CTLA-4 antibody therapy, including as most recent therapy in combination with anti-PD-(L)1 therapy, is permitted but not required.
- Confirmed progressive disease on anti-PD-(L)1 antibody therapy
7. Evaluable disease per RECIST 1.1 with at least two target lesions as defined by RECIST 1.1. Both injectable and non-injectable target lesions should be chosen for efficacy evaluation.
8. For the Phase 2 expansion portions of the study, a maximum of 3 prior lines of systemic treatment for locally advanced or metastatic disease. (This criterion does not apply to the optional exploratory expansion cohort.)
9. For female patients of childbearing potential, defined as females who 1) have not undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy or 2) have not been postmenopausal for at least 12 consecutive months [i.e., have had menses at any time during the preceding 12 consecutive months]):
- Willing to use one of the following effective methods of contraception for at least 30 days before administration of cavrotolimod, during treatment with cavrotolimod, pembrolizumab, or cemiplimab, and for at least four months after the last dose of cavrotolimod, pembrolizumab, or cemiplimab:
- Total abstinence from sexual intercourse with a partner that may result in pregnancy
- Hormonal contraception (oral, parenteral, or transdermal) used for at least 3 consecutive months prior to the first dose of cavrotolimod
- Intrauterine contraceptive device
- Barrier contraception (i.e., condom, cap, diaphragm, or sponge with spermicide)
For male patients who have not had a vasectomy:
- Willing to use one of the following effective methods of contraception for at least 30 days before administration of cavrotolimod, during treatment with cavrotolimod, pembrolizumab, or cemiplimab, and for at least four months after the last dose of cavrotolimod, pembrolizumab, or cemiplimab:
- Total abstinence from sexual intercourse with a female partner of childbearing potential
- Use by female partner of hormonal contraception (oral, parenteral, or transdermal) for at least 3 consecutive months prior to the first dose of cavrotolimod
- Use by female partner of intrauterine contraceptive device
- Barrier contraception (i.e., condom, cap, diaphragm, or sponge with spermicide)
10. Regarding history of CPI-related adverse events:
- Resolution of CPI-related AEs (including irAEs) to G0-1 and no corticosteroids for the amelioration of those irAEs for at least 4 weeks prior to the first dose of cavrotolimod. Controlled hypothyroidism and controlled adrenal insufficiency are exceptions to this criterion, provided doses do not exceed the threshold described in exclusion criterion #13.
- No history of CTCAE G4 irAEs from CPI. iii. No history of CTCAE G3 irAEs from CPI. Patients with a history of CTCAE G3 irAEs from CPI requiring steroid treatment for no greater than 12 weeks may be considered at the discretion of the Investigator if supported by an assessment of risk-benefit and after discussion with the Medical Monitor.
11. Adequate organ function.
12. Able and willing to comply with the protocol and the restrictions and assessments therein.
NCT ID
NCT03684785