Clinical trial NCT04698187: CMP-001 in Combination With Nivolumab in Subjects With Advanced Melanoma
Official title: A Multicenter, Open-label, Phase 2 Study of Intratumoral CMP-001 in Combination With Intravenous Nivolumab in Subjects With Refractory Unresectable or Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Melanoma
Advanced Melanoma
Metastatic Melanoma
Unresectable Melanoma
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2021-01-06
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: CMP-001-010 is a Phase 2 study of CMP-001 intratumoral (IT) and nivolumab intravenous (IV) administered to participants with refractory unresectable or metastatic melanoma.

The primary objective of the study is to determine confirmed objective response with CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.

The secondary objectives are to:

* To evaluate the safety and tolerability of CMP-001 administered by intratumoral (IT) injection in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To evaluate the efficacy of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To assess the pharmacokinetic (PK) profile of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.
* To assess and describe the immunogenicity of CMP-001 in combination with nivolumab in subjects with refractory unresectable or metastatic melanoma.

Detailed description: Former Sponsor Checkmate Pharmaceuticals

Eligibility criteria: Inclusion Criteria:

Subjects enrolled in the study must meet all of the following inclusion criteria to be eligible.

1. Histopathologically-confirmed diagnosis of malignant melanoma that is metastatic or unresectable at Screening.
2. Known BRAF mutation status; if BRAF V600 mutation positive, must have had prior treatment with a local Health Authority approved BRAF inhibitor, with or without mitogen-activated protein kinase inhibitor. Patients with BRAF V600 mutations who refuse a BRAF inhibitor will not be eligible.
3. Refractory to PD-1 blockade either as monotherapy or in combination with other therapies, as defined by the following criteria:

   1. Received treatment with a Food and Drug Administration approved PD-1 blocking antibody for 12 weeks or longer.
   2. Have PD (according to RECIST v1.1) within 12 weeks of the last dose of a PD-1 blocking antibody, either as monotherapy or in combination with other agents.

   Evidence of confirmed PD must be established by investigator assessment at least 4 weeks after the initial date of PD. The second assessment may serve as the Baseline for this study if completed within 30 days before to the start of study treatment. NOTE: in subjects with histologically confirmed recurrence on or after adjuvant PD-1 blocking antibody, confirmatory imaging is not required.
4. Measurable disease, as defined by RECIST v1.1 and all of the following:

   1. At least 1 accessible lesion amenable to repeated IT injection.
   2. One or more measurable lesions at least 1 cm in diameter that are not intended for CMP 001 injection and can be followed as target lesions per RECIST v1.1.
   3. Documented disease progression in any lesion that was previously radiated in order to serve as a target lesion.
5. Able to provide tissue from a core or excisional biopsy (fine needle aspirate is not sufficient). A fresh tissue biopsy (within 90 days before the start of study treatment) is preferred but an archival sample is acceptable if no intervening therapy was received. Note: For tissue sampling details, please refer to the laboratory manual.
6. Adequate organ function based on most recent laboratory values within 3 weeks before first dose of study treatment on Week 1 Day 1 (W1D1):

   1. Bone marrow function:

      * neutrophil count ≥ 1500/mm3
      * platelet count ≥ 100,000/mm3
      * hemoglobin concentration ≥ 9 g/dL
      * white blood cells ≥ 2000/mm3
   2. Liver function:

      * total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following exception: patients with Gilbert Disease total serum bilirubin ≤ 3 times ULN
      * aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN
   3. Lactate dehydrogenase ≤ 2 times the ULN
   4. Renal function: estimated (Cockcroft-Gault) or measured creatinine clearance ≥ 30 mL/min.
   5. Coagulation:

      * International normalized ratio or prothrombin time (PT) ≤ 1.5 times ULN, unless subject is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
      * Activated partial thromboplastin time or PTT ≤ 1.5 times ULN, unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
7. Age ≥ 18 years at time of consent.
8. Eastern Cooperative Oncology Group Performance Status of 0 to 1 at Screening.
9. Capable of understanding and complying with protocol requirements.
10. Women of childbearing potential must have negative serum pregnancy test before dosing at W1D1 and be willing to use an adequate method of contraception from the time of consent until at least 150 days after last dose of study treatment.
11. Able and willing to provide written informed consent and to follow study instructions. Subjects unable to provide written informed consent on their own behalf will not be eligible for the study.

Exclusion Criteria:

Subjects presenting with any of the following will not qualify for entry into the study:

1. Uveal, acral, or mucosal melanoma.
2. Received radiation therapy (or other nonsystemic therapy) within 2 weeks before first dose of study treatment on W1D1. Patients should have recovered (ie, Grade ≤1 or at baseline) from radiation-related toxicities.
3. Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before start of study treatment. Refer to Section 4.4. for prohibited therapies.
4. Received systemic pharmacologic doses of corticosteroids ≥10 mg/day prednisone within 30 days before first dose of study treatment on W1D1.

   1. Subjects who are currently receiving steroids at a prednisone-equivalent dose of ≤ 10 mg/day do not need to discontinue steroids before enrollment.
   2. Replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
   3. Stress-dose corticosteroids will be required in subjects with adrenal insufficiency
5. History of immune-related AE that required permanent discontinuation of PD-1 blocking antibody.
6. Not fully recovered from AEs (to Grade 1 or less \[per CTCAE v5.0\], with the exception of persistent adverse events or sequelae, eg, vitiligo, alopecia, hypothyroidism, diabetes mellitus, and adrenal and/or pituitary insufficiency) due to prior treatment.

   NOTE: Subjects previously treated with a CTLA-4-blocking antibody, subjects receiving corticosteroids with daily doses \> 5 mg and ≤ 10 mg of prednisone equivalent for 2 weeks, and subjects with clinical symptoms and/or laboratory findings suggesting risk for adrenal insufficiency should undergo diagnostic tests for adrenal insufficiency via local laboratory.
7. Active pneumonitis or history of noninfectious pneumonitis that required steroids.
8. Severe uncontrolled cardiac disease within 6 months of Screening, including but not limited to poorly controlled hypertension, unstable angina, myocardial infarction, congestive heart failure (New York Heart Association Class II or greater), pericarditis within the previous 6 months, cerebrovascular accident, or implanted or continuous use of a pacemaker or defibrillator.
9. Known history of immunodeficiency.
10. Known additional malignancy that is progressing or required active treatment within the past 3 years. Exceptions include cancers that have undergone potentially curative therapy, eg, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer with prostate-specific antigen level below 4.0 ng/mL, in situ cervical cancer on biopsy or a squamous intraepithelial lesion on Papanicolaou smear, and thyroid cancer (except anaplastic), in situ breast cancer, and adjuvant hormonal therapy for breast cancer \> 3 years from curative-intent surgical resection.
11. Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment.
12. Untreated, symptomatic, or enlarging central nervous system metastases or carcinomatous meningitis (including leptomeningeal metastases from solid tumors).
13. Prior allogenic tissue/solid organ transplant.
14. Active infection requiring systemic therapy.
15. Known or suspected active infection with severe acute respiratory syndrome coronavirus 2 virus.
16. Known or suspected active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus (testing is not required unless suspected).
17. Received a live virus/attenuated vaccination within 30 days before first dose of study treatment on W1D1.
18. Received blood products (including platelets or red blood cells) or colony stimulating factors (including granulocyte colony stimulating factor, granulocyte/macrophage colony stimulating factor, or recombinant erythropoietin) within 30 days before the start of Screening.
19. History of allergy or hypersensitivity to nivolumab and/or any of its excipients.
20. Any concurrent uncontrolled illness, including mental illness or substance abuse, which in the opinion of the Investigator would make the subject unable to cooperate or participate in the study.
21. Participation in another clinical study of an investigational anticancer therapy or device within 30 days before first dose of study treatment on W1D1. Participation in the follow-up phase (receiving no study treatment) of a prior study is allowed.
22. Requires prohibited treatment (ie, non-protocol specified anticancer pharmacotherapy, surgery, or radiotherapy) for treatment of malignant tumor.
23. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating Investigator.
24. Received previous CMP-001 treatment.
25. Pregnant or breastfeeding or expecting to conceive or donate eggs within the projected duration of the study, from the time of consent until at least 150 days after last dose of study treatment for women.

Primary outcomes:
measure: Confirmed Objective Response Rate (ORR) by Blinded Independent Central Review (BICR)
timeFrame: Up to approximately 24 months (107 weeks)
Secondary outcomes:
measure: Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Any Serious TEAE, and Any TEAE Leading to Discontinuation or Death
timeFrame: Up to approximately 24 months (107 weeks)
measure: Severity of TEAEs as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
timeFrame: Up to approximately 24 months (107 weeks)
measure: Time to Response (TTR) by BICR
timeFrame: Up to approximately 28 months (122 weeks)
measure: Time to Response (TTR) by Investigator
timeFrame: Up to approximately 28 months (122 weeks)
measure: Duration of Response (DOR) by BICR
timeFrame: Up to approximately 28 months (122 weeks)
measure: Duration of Response (DOR) by Investigator
timeFrame: Up to approximately 28 months (122 weeks)
measure: Confirmed ORR in Non-injected Target Lesions by Investigator
timeFrame: Up to approximately 24 months (107 weeks)
measure: Progression-free Survival (PFS) by BICR
timeFrame: Up to approximately 31 months (135 weeks)
measure: Progression-free Survival (PFS) by Investigator
timeFrame: Up to approximately 31 months (135 weeks)
measure: Overall Survival (OS) by Investigator
timeFrame: Up to approximately 32 months (139 weeks)
measure: Immune Objective Response Rate (iORR) by Investigator
timeFrame: Up to approximately 24 months (107 weeks)
measure: Immune Duration of Response (iDOR) by Investigator
timeFrame: Up to approximately 28 months (122 weeks)
measure: Immune Progression-free Survival (iPFS) by Investigator
timeFrame: Up to 9 months (approximately 39 weeks)
measure: Maximum Observed Serum Concentration
timeFrame: From first dose of drug (Week 1 Day 1) until 30 days after the last drug injection (until a reason for treatment discontinuation occurs)
measure: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Quantifiable Time Point
timeFrame: From first dose of drug (Week 1 Day 1) until 30 days after the last drug injection (until a reason for treatment discontinuation occurs)
measure: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity
timeFrame: From first dose of drug (Week 1 Day 1) until 30 days after the last drug injection (until a reason for treatment discontinuation occurs)
measure: Terminal Elimination Half-Life
timeFrame: From first dose of drug (Week 1 Day 1) until 30 days after the last drug injection (until a reason for treatment discontinuation occurs)
measure: Number of Participants With Immunogenicity as Measured by Anti-Qbeta Antibodies (ADA)
timeFrame: Up to approximately 24 months (107 weeks)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical Center, Robert Kang, MD
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology-Oncology
state: California
city: San Marcos
country: United States
facility: California Cancer Associates for Research & Excellence, Inc.
state: California
city: Denver
country: United States
facility: University of Colorado- Denver
state: Colorado
city: Hartford
country: United States
facility: Hartford Healthcare
state: Connecticut
city: Jacksonville
country: United States
facility: GenesisCare USA
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Athens
country: United States
facility: University Cancer & Blood Center
state: Georgia
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Louisville
country: United States
facility: University of Louisville Health Care
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Herbert Irving Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Sammons Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah- Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: