Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at Orange, California and other locations
Dates
study started
estimated completion

Description

Summary

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. Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of cavrotolimod given with a fixed dose of pembrolizumab. The Phase 2 dose expansion part of the study will consist of two cohorts of patients: Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (CSCC). Patients in the MCC cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the CSCC cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab. The Phase 2 dose expansion is designed to provide a preliminary estimate of efficacy in patients that have progressed on an anti-PD-(L)1 CPI.

Official Title

A Phase 1b/2 Study of Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Advanced Solid Tumors

Details

This study will be conducted in 2 phases. Phase 1 evaluates cavrotolimod 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 cavrotolimod and enrollment of at least 3 patients per cohort to identify an RP2D. Patients will be dosed twice with cavrotolimod 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 2-stage expansion cohort design will be initiated. Phase 2 will evaluate the RP2D of cavrotolimod 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. Patients in the MCC cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the CSCC cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab. Phase 2 will include an exploratory expansion cohort to evaluate cavrotolimod in combination with pembrolizumab in patients with other advanced solid tumors, including melanoma, who have progressed on anti-PD-(L)1 therapy.

Keywords

Advanced or Metastatic Merkel Cell Carcinoma Advanced or Metastatic Cutaneous Squamous Cell Carcinoma Advanced or Metastatic Melanoma Advanced or Metastatic Head and Neck Squamous Cell Carcinoma Advanced or Metastatic Solid Tumors Skin Cancer Head and Neck Squamous Cell Carinoma Cutaneous Squamous Cell Carcinoma Merkel Cell Carcinoma Melanoma Carcinoma, Merkel Cell Carcinoma Carcinoma, Squamous Cell Squamous Cell Carcinoma of Head and Neck Pembrolizumab Cemiplimab Cavrotolimod

Eligibility

You can join if…

Open to people ages 18 years and up

  1. Written informed consent.
  2. Male or female ≥18 years of age.
  3. Must have an advanced inoperable histologically diagnosed solid tumor.
  4. Phase 2 MCC Expansion Cohort: locally advanced or metastatic Merkel cell caricinoma
  5. Phase 2 CSCC Expansion Cohort: locally advanced or metastatic cutaneous squamous cell carcinoma
  6. Phase 2 Exploratory Expansion Cohort: locally advanced or metastatic Merkel cell carcinoma or advanced or metastatic melanoma
  7. At least one tumor lesion amenable to repeated IT injection via palpation or ultrasound. Injection of deep visceral lesions is not permitted
  8. 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.
  9. 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:

  1. 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.

ii. Confirmed progressive disease during treatment with avelumab or pembrolizumab therapy,

Phase 2 CSCC Expansion Cohort

  1. 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.

ii. Confirmed progressive disease on cemiplimab or pembrolizumab therapy

Phase 2 Exploratory Expansion Cohort(s):

  1. 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.

ii. Confirmed progressive disease on anti-PD-(L)1 antibody therapy

  1. 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.
  2. 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.)
  3. 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:

  1. Total abstinence from sexual intercourse with a partner that may result in pregnancy

ii. Hormonal contraception (oral, parenteral, or transdermal) used for at least 3 consecutive months prior to the first dose of cavrotolimod

iii. Intrauterine contraceptive device

iiii. 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:

  1. Total abstinence from sexual intercourse with a female partner of childbearing potential

ii. Use by female partner of hormonal contraception (oral, parenteral, or transdermal) for at least 3 consecutive months prior to the first dose of cavrotolimod

iii. Use by female partner of intrauterine contraceptive device

iiii. Barrier contraception (i.e., condom, cap, diaphragm, or sponge with spermicide)

  1. . Regarding history of CPI-related adverse events:
  2. 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.

ii. 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.

  1. . Adequate organ function.
  2. . Able and willing to comply with the protocol and the restrictions and assessments therein.

You CAN'T join if...

  1. Small molecule or tyrosine kinase inhibitor within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of cavrotolimod, chemotherapy or biological cancer therapy within 3 weeks prior to the first dose of cavrotolimod, nitrosourea, or radioisotope within 6 weeks prior to first dose of cavrotolimod, 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, cemiplimab or another anti-PD-(L)1 monoclonal antibody.
  4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1.
  5. Symptomatic ascites or pleural effusion. A patient with these conditions who has received treatment such as therapeutic thoracentesis or paracentesis and is clinically stable, defined as not requiring repeat drainage procedure within 2 weeks, may be considered after discussion with the Medical Monitor.
  6. 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 the first dose of cavrotolimod, have no evidence of new or enlarging brain metastases and are off steroids for at least 14 days prior to the first dose of cavrotolimod.
  7. 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), with the following exceptions: 1) patients who have undergone potentially curative therapy with no evidence of that disease for 3 years prior to the first dose of cavrotolimod; 2) 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; 3) stable chronic lymphocytic leukemia not requiring treatment within 3 years prior to the first dose of cavrotolimod.
  8. Active autoimmune disease or a documented history of autoimmune disease within the 2 years prior to the first dose of cavrotolimod that requires or required 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.
  9. Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15 days or other immunosuppressive drugs within 30 days prior to the first dose of cavrotolimod. Inhaled and topical corticosteroids are permitted. Up to 10 mg/day prednisone or equivalent is permitted for hypothyroidism or adrenal insufficiency.
  10. . Received an investigational product or been treated with an investigational device within 30 days prior to the first dose of cavrotolimod or will start any other investigational product or device study within 30 days after last study drug administration.
  11. . 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.
  12. . Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through 4 months after the last dose of cavrotolimod, pembrolizumab, or cemiplimab.

Locations

  • University of California Irvine not yet accepting patients
    Orange California 92868 United States
  • John Wayne Cancer Institute / Providence St. John's Health Center accepting new patients
    Santa Monica California 90401 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Exicure, Inc.
Links
Exicure homepage
ID
NCT03684785
Phase
Phase 1/2
Study Type
Interventional
Last Updated