Neoadjuvant Immunotherapy With Tavo + Electroporation in Combination With Nivo. in Melanoma Patients

• ClinicalTrials.gov Identifier: NCT04526730
• Recruitment Status: Recruiting
• First Posted: August 26, 2020
• Last Update Posted: April 14, 2023
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborator: OncoSec Medical Incorporated
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Tracking Information

• First Submitted Date: August 21, 2020
• First Posted Date: August 26, 2020
• Last Update Posted Date: April 14, 2023
• Actual Study Start Date: December 22, 2020
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 21, 2020)

Pathological Complete Response [ Time Frame: Up to 16 weeks after start of therapy ]

Pathological Complete Response will be will be estimated based on the proportion of participants with no viable tumor on histologic assessment at definitive surgery after the 12 week Neoadjuvant phase. Surgery will then be scheduled 2-4 weeks after neoadjuvant phase.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 25, 2020)

• Objective Response Rate [ Time Frame: 12 weeks after start of therapy ]
  ORR assessed by Investigator based on RECIST v1.1 at 12 weeks during the Neoadjuvant phase
• Relapse Free Survival [ Time Frame: 12 weeks after start of therapy ]
  RSF assessed by Investigator based on RECIST v1.1 at 12 weeks during the Neoadjuvant phase
• Overall Survival [ Time Frame: Up to 5 years after start of therapy ]
  Overall survival at 5 years after start of therapy
• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Up to 5 years after start of therapy ]
  To determine the safety and tolerability of combined treatment as neoadjuvant therapy will be based on the frequency of AEs
• Risk of Surgical Delay [ Time Frame: Up to 16 weeks after start or therapy ]
  Definitive surgery will be planned at about 12 weeks. Participants will be monitored for surgical delay (either due to toxicity and/or tumor progression).

Original Secondary Outcome Measures (submitted: August 21, 2020)

• Objective Response Rate [ Time Frame: 12 weeks after start of therapy ]
  ORR assessed by Investigator based on RECIST v1.1 at 12 weeks during the Neoadjuvant phase
• Relapse Free Survival [ Time Frame: 12 weeks after start of therapy ]
  RSF assessed by Investigator based on RECIST v1.1 at 12 weeks during the Neoadjuvant phase
• Overall Survival [ Time Frame: Up to 5 years after start of therapy ]
  Overall survival at 5 years after start of therapy
• Safety and Tolerability [ Time Frame: Up to 5 years after start of therapy ]
  To determine the safety and tolerability of combined treatment as neoadjuvant therapy will be based on the frequency of AEs
• Risk of Surgical Delay [ Time Frame: Up to 16 weeks after start or therapy ]
  Definitive surgery will be planned at about 12 weeks. Participants will be monitored for surgical delay (either due to toxicity and/or tumor progression).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neoadjuvant Immunotherapy With Tavo + Electroporation in Combination With Nivo. in Melanoma Patients
• Official Title: Neoadjuvant Immunotherapy With Intratumoral Tavokinogene Telseplasmid (Tavo) Plus Electroporation in Combination With Intravenous Nivolumab in Patients With Operable Locally- Regionally Advanced Melanoma
• Brief Summary: This is a Phase 2 open-label, single-arm study of neoadjuvant treatment of intratumoral tavo-EP plus nivolumab IV infusion. Eligible participants will be those with pathological diagnosis of operable locally-regionally advanced melanoma.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: Tavo
  Tavo will be injected on Days 1 and 8 every 4 weeks at a dose volume of ¼ of the calculated lesion volume with a minimum dose volume per lesion of 0.1 mL for lesions of volume <0.4 cm3
• Drug: Nivolumab
  Nivolumab will be administered 480 mg every 4 weeks over 30 minute infusions
• Device: OncoSec Medical Electroporation Therapy System

  The OMS (OncoSec Medical Electroporation Therapy System), a medical EP device system, consists of 3 components: 1. an Electroporation Generator that generates electric pulses, 2. a sterile Applicator Tip containing needle array, and 3. an Applicator Handle that connects to the Electroporation Generator at the proximal end and connects to the Applicator Tip at the distal end.

  Upon user activation of the attached Foot Switch, the OMS Electroporation Generator delivers controlled electrical pulses in a square wave pulse pattern yielding optimal transmembrane potential for electroporation to occur. EP pulses occur between 6 hexagonal opposing needle electrodes. After the first pulse, the polarity between the opposing needle electrode pairs is reversed and the needle pair is pulsed again. After the initial paired pulse, the pulse delivery is rotated clockwise to the next opposing needle pairs until a total of 6 pulses are delivered to complete the EP sequence.

  Other Name: Electroporation

Study Arms

Experimental: Neoadjuvant Treatment

Neoadjuvant Phase: (3 x 4-week cycles, total 12 weeks): At every cycle, intratumoral tavo-EP will be administered (on Days 1 and 8) concurrently with 480 mg nivolumab IV infusion on Day 8 of each cycle (tavo-EP will be administered prior to nivolumab infusion).

Definitive Surgery Phase: Surgery may be scheduled about 2-4 weeks after the last dose of nivolumab following radiologic and clinical assessment at that point. Pathologic response will be determined by institutional pathologist.

Adjuvant Phase: Adjuvant therapy with nivolumab monotherapy will begin approximately 2-4 weeks following definitive surgery; recovery from surgery is required (Day 1 of Cycle 4 will be determined by the treating investigator once the subject is cleared to initiate systemic therapy). Nivolumab (480 mg IV infusion on Day 1 of each 4-week cycle) will be administered for up to 9 cycles during the Adjuvant phase.

Interventions:

• Drug: Tavo
• Drug: Nivolumab
• Device: OncoSec Medical Electroporation Therapy System

• Publications *: Jacobs L, Yshii L, Junius S, Geukens N, Liston A, Hollevoet K, Declerck P. Intratumoral DNA-based delivery of checkpoint-inhibiting antibodies and interleukin 12 triggers T cell infiltration and anti-tumor response. Cancer Gene Ther. 2022 Jul;29(7):984-992. doi: 10.1038/s41417-021-00403-8. Epub 2021 Nov 9.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 21, 2020): 33
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2023
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participant must be ≥ 18 years of age inclusive, at the time of signing the informed consent
• Histologic diagnosis of melanoma

• Must be considered surgically operable and may present as any of the following groups:

  1. Primary melanoma with clinically apparent regional lymph node metastases, confirmed by pathological diagnosis.
  2. Clinically detected recurrence of melanoma at regional lymph node basin(s), confirmed by pathological diagnosis.
  3. Clinically or histologically detected primary melanoma involving multiple regional nodal groups, confirmed by pathological diagnosis.
  4. Clinically detected single site of nodal metastatic melanoma arising from an unknown primary, confirmed by pathological diagnosis.
  5. Participants with in transit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at Screening by the treating surgical oncologist.
  6. Participants with distant cutaneous/subcutaneous, soft tissue or nodal metastases with or without regional lymph node involvement are allowed if they are considered potentially surgically resectable and can be biopsied at Screening by the treating surgical oncologist. Elevated LDH is not an exclusion.
• Participants are eligible for this study either at presentation for primary melanoma with concurrent regional nodal and/or in-transit or distant metastasis, or at the time of clinically detected nodal, in transit, or distant recurrence
• Participants must be evaluated by standard-of-care full body imaging studies including positron emission tomography - computed tomography (PET-CT ;preferred; including diagnostic CT component if possible) or CT (if PET-CT cannot be done) as well as magnetic resonance imaging (MRI) of the brain (or CT if MRI cannot be done) as part of the initial clinical work-up at Screening (no more than 4 weeks prior to Cycle 1, Day 1).

• Have measurable disease based on RECIST v1.1, with at least one anatomically distinct lesion. Lesion or lesions must meet all the following baseline criteria:

  1. Accessible for electroporation
  2. Must be measured in at least one dimension (longest diameter in the plane of measurement is to be recorded)
  3. Greater than 3 mm
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male Participants: Male subjects of childbearing potential must be surgically sterile, or must agree to use adequate method of contraception during the study and at least 5 months following the last day of study drug administration. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Female participants: Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and 5 months following last day study drug administration (either tavo or nivolumab); acceptable methods include hormonal contraception (oral contraceptives - as long as on stable dose, patch, implant, and injection), intrauterine devices, or double barrier methods (e.g. vaginal diaphragm/vaginal sponge plus condom, or condom plus spermicidal jelly), sexual abstinence or a vasectomized partner. Women may be surgically sterile or at least 1-year post-last menstrual period. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion Criteria:

• Participant has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Also, includes patients who are considered disease-free for at least 3 years from the last definitive treatment for a second malignancy.
• Participants who have Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies at Screening). HIV testing at screening is not required unless considered clinically indicated by the treating physician.
• Participants who have active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected at Screening); Note: Participants who have been vaccinated against Hepatitis B and who are positive only for the Hepatitis B surface antibody are permitted to participate in the study. Hepatitis B and C testing at screening is not required unless considered clinically indicated by the treating physician.
• Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Principal Investigator.
• Participant has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Participant has a history of interstitial lung disease.
• Participant has an active infection requiring systemic therapy.
• Participant has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Participant has not recovered (i.e., > Grade 1 at Cycle 1, Day 1) from AEs due to a previously administered agent.
• Participant has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
• Participants who are pregnant or breast feeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 5 months after the last dose of trial treatment.
• Participants with electronic pacemakers or defibrillators
• Participants who have received a live-virus vaccination within 30 days of the first dose of treatment. Seasonal flu vaccines that do not contain live virus are permitted
• Participants who have received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1.
• Previous treatment with anti-PD1 or anti-PDL1 immunotherapy.
• Participation in another clinical study and systemic therapy within 30 days of Cycle 1, Day 1.
• ECOG Performance Status: >1
• Inadequate organ function as defined per protocol
• Participant has severe hypersensitivity (≥Grade 3) to nivolumab and/or any of its excipients

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Deanryan Deaquino; 813-745-3998; Deanryan.Deaquino@moffitt.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04526730
• Other Study ID Numbers: MCC-20313
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Original Study Sponsor: Same as current
• Collaborators: OncoSec Medical Incorporated

Investigators

• Principal Investigator: Ahmad Tarhini, MD, PhD; Moffitt Cancer Center

• PRS Account: H. Lee Moffitt Cancer Center and Research Institute
• Verification Date: April 2023