A Study of Intratumoral CAVATAK™ in Patients With Stage IIIc and Stage IV Malignant Melanoma (VLA-007 CALM ) (CALM)

A Phase 2 Study of the Efficacy and Safety of Intratumoral CAVATAK™ (Coxsackievirus A21, CVA21) in Patients With Stage IIIc and Stage IV Malignant Melanoma (VLA-007 CALM )

The purpose of this study is to assess the clinical efficacy of Intratumoral (IT) CVA21 in terms of immune-related Progression-Free Survival (irPFS) at 6 months as monitored via immune-related Response Criteria [irRECIST 1.1] (revised Response Evaluation Criteria In Solid Tumors [RECIST] 1.1).

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Biological: Coxsackievirus A21 (CVA21)

Detailed Description

This is a multicenter, open-label, 2-stage, single-arm efficacy and safety study. Approximately 63 patients with histologically proven stage IIIc or stage IV melanoma who fail to qualify for curative surgery and who bear one or more tumors that are accessible for direct injections and at least one measurable lesion by RECIST 1.1 criteria will be considered.

Prospective patients will attend the study center for initial screening within 28 days prior to treatment with CVA21. They will have the nature of the study and its procedures and risks fully explained. All patients must provide a written informed consent to participate in the study.

The dose of CVA21 for this study is 3 x 108 TCID50 (about 4.5 x 106 TCID50/kg for a 70-kg patient) by IT administration. Each patient will receive 4 separate CVA21 administrations in the first 8 days on trial (Days 1, 3, 5 and 8), followed by a fifth dose 2 weeks later (Day 22) and further administrations at 3 weekly intervals (Days 43, 64, 85, 106 and 127, up to a maximum of 10 sets of injections) or until confirmed disease progression or development of excessive toxicity.

Disease status will be assessed by contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) scan and/or direct caliper measurement (and ultrasound assistance, if necessary) and categorized by immune-related RECIST 1.1 criteria prior to commencing treatment (baseline) and at Days 43, 85, 127 and 169 and 12-weekly intervals thereafter until disease progression. At 2 years, intervals can increase to 6 months.

At 12 weeks post-commencement of treatment (Day 85), if a patient's disease status is classed as progressive disease (but without rapid clinical deterioration) the patient may remain on the trial for a further 6 weeks, when his/her disease status will be confirmed prior to the scheduled treatment. If disease progression is confirmed, the patient will cease treatment but will remain on the study and be observed for efficacy and safety until initiation of treatment with non-CVA21 anticancer therapies. However, survival will be followed until death. If stable disease or better (CR or PR) is observed at this time, the patient will continue treatment as per the protocol. Complete and partial responses will be confirmed at the next contrast-enhanced CT or MRI scan analysis.

Patients who have evidence of biologic activity, i.e., tumor inflammatory reaction and/or stable disease or better, at 18 weeks (Day 127) are eligible to participate in the extension trial in which they will continue to receive IT injections of CVA21 every 3 weeks up to a total of 1 year of therapy from the first injection.

Throughout the trial, immunological responses to the tumor and CVA21 will be monitored.

After the full CVA21 injection schedule has been completed, patients will be followed at 12-weekly intervals beginning on Day 169 for a total of 12 months according to the schedule for safety assessment and indefinitely for survival. Patients with progressive disease (but without rapid clinical deterioration) at 6 months (Day 169) will have a further tumor assessment 6 weeks later for confirmation or continuation of observation for duration of disease control and all subjects will be followed for survival. Patients who are withdrawn from treatment with CVA21 during the treatment phase must also be followed up every 6 weeks for 12 weeks for safety and for survival.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • Moores UCSD Cancer Center
    • San Francisco, California, United States, 94117
      • St Mary's Medical Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Niles, Illinois, United States, 60714
      • Oncology Specialists, SC
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Investigative Clinical Research of Indiana
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Atlantic Melanoma Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Cancer Center
  • Texas
    • Dallas, Texas, United States, 75201
      • Mary Crowley Cancer Research Centers
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patient with histologically proven stage IIIc or stage IV melanoma who fails to qualify for curative surgery and who bears one or more tumors that are accessible for direct injection
2. Patient must have had no more than one previous systemic regimen for management of melanoma; however, adjuvant chemotherapy administered 6 months or longer before entering the trial does not count as a line of treatment
3. Absence of circulating serum neutralizing antibodies to CVA21 (titer < 1:16)
4. At least one tumor 0.5 to 10 cm in the longest diameter must be suitable for injection and at least one tumor must be equal to or greater than 1 cm and qualified to be a target lesion for RECIST 1.1 criteria

5. Patient must have adequate hematologic, hepatic and renal function, defined as:

   • Absolute neutrophil count (ANC) > 1.5 x 10^9/L, platelets > 100 x 10^9/L
   • Bilirubin < 1.5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) < 2.5 x ULN
   • Serum creatinine < 1.5 x ULN; if > 1.5 x ULN, it must be confirmed that creatinine clearance > 30 mL/minute
6. Serum lactate dehydrogenase (LDH) levels < or = 1.5 x ULN
7. Male or female age 18 years or older
8. Performance status (Eastern Cooperative Oncology Group [ECOG]) 0 or 1
9. Estimated life expectancy of more than 6 months
10. Recovered from prior therapy with at least 4 weeks since the last exposure to chemotherapy or radiotherapy
11. Patient is able and willing to provide written informed consent to participate in the study
12. Fertile males and females must agree to the use of an adequate form of contraception, e.g., condoms for males. A negative pregnancy test is required in female patients of childbearing potential.

Exclusion Criteria:

1. Mucosal or ocular primary tumors
2. Bone metastases
3. Greater than 3 visceral metastases
4. Any visceral metastases > 10 cm
5. Serum anti-CVA21 neutralizing titer of > 1:16 at baseline
6. Presence of any central nervous system (CNS) tumor that has not been stable for at least 3 months off corticosteroids and confirmed by imaging
7. Tumors to be injected lying in mucosal regions or close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigators, could cause occlusion into a major vessel in the case of necrosis
8. Only measurable tumor had prior local radiotherapy without subsequent nodule progression
9. Patient has received chemotherapy within the last 4 weeks prior to first injection
10. ECOG score greater than 1
11. Estimated life expectancy of less than 6 months
12. Pregnancy or breastfeeding
13. Primary or secondary immunodeficiency, including immunosuppressive disease, and immunosuppressive doses of corticosteroids (e.g., prednisolone > 7.5 mg per day) or other immunosuppressive medications including cyclosporine, azathioprine, interferons within the past 4 weeks prior to screening
14. Positive serology for human immunodeficiency virus (HIV), hepatitis B or C
15. Full dose anticoagulation or a history of bleeding diathesis or poorly controlled bleeding in the last month prior to screening
16. Previous splenectomy
17. Presence of uncontrolled infection
18. Presence of unstable neurological disease
19. Any uncontrolled medical condition that, in the opinion of the investigator, is likely to place the patient at unacceptable risk during the study or reduce his/her ability to complete the study
20. Participation in another study requiring administration of an investigational drug or biological agent within the last 4 weeks prior to screening
21. Any other medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
22. Participation in any previous melanoma immunotherapy trial within 1 month prior to entry to this trial or any trial of any other investigational agent within the last month prior to entry to this trial
23. Active infections or serious general medical conditions
24. Patients with previous malignancies should only be permitted if they have been in a continued state of "no evidence of disease" for at least 5 years with the exception of adequately treated carcinoma in situ of the cervix, ductal carcinoma in situ (DCIS) of the breast, and basal cell/squamous cell skin cancer
25. Known allergy to treatment medication or its excipients and/or to the contrast medium

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Intratumoral injection; Each patient will receive 4 separate Coxsackievirus A21 (CVA21) administrations in the first 8 days on trial (Days 1, 3, 5 and 8), followed by a fifth dose 2 weeks later (Day 22) and further administrations at 3 weekly intervals (Days 43, 64, 85, 106 and 127, up to a maximum of 10 sets of injections) until confirmed disease progression or development of excessive toxicity. Subjects with stable disease or better at Day 127 were eligible to receive up 9 more sets of CVA21 administrations under an extension protocol (VLA-008).

Biological: Coxsackievirus A21 (CVA21); CVA21 is a live oncolytic virus preparation derived from the non-genetically altered prototype Kuykendall strain of Coxsackievirus A21.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Immune-related Progression-Free Survival (irPFS) at 6 Months	To assess the clinical efficacy of Intratumoral (IT) CVA21 in terms of immune-related Progression-Free Survival (irPFS) at 6 months.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durable Response Rate	Per Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI or calipers: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Durable Response Rate (DRR) = CR + PR.	6 months or more

Collaborators and Investigators

• Sponsor: Viralytics
• Investigators: Principal Investigator: Robert Andtbacka, MD, Associate professor

Publications and helpful links

General Publications

• Andtbacka RHI, Curti B, Daniels GA, Hallmeyer S, Whitman ED, Lutzky J, Spitler LE, Zhou K, Bommareddy PK, Grose M, Wang M, Wu C, Kaufman HL. Clinical Responses of Oncolytic Coxsackievirus A21 (V937) in Patients With Unresectable Melanoma. J Clin Oncol. 2021 Dec 1;39(34):3829-3838. doi: 10.1200/JCO.20.03246. Epub 2021 Aug 31.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 29, 2011
• Primary Completion (ACTUAL): April 6, 2016
• Study Completion (ACTUAL): April 6, 2016

Study Registration Dates

• First Submitted: October 20, 2010
• First Submitted That Met QC Criteria: October 22, 2010
• First Posted (ESTIMATE): October 25, 2010

Study Record Updates

• Last Update Posted (ACTUAL): July 5, 2019
• Last Update Submitted That Met QC Criteria: June 24, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Melanoma; CALM
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: V937-006; VLA-007 (OTHER: Viralytics Study ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO