Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV
Conditions
Keywords
Unresectable, Melanoma, pDNA, Plasmid DNA, Gene Therapy
Brief summary
Six patients will receive IFx-Hu2.0 on an outpatient basis at a single time point in a single lesion, two lesions, or three lesions, as a monotherapy (a maximum of three lesions could be injected). These patients will be assessed for any immediate adverse reactions and at Week 4 (Day 28+/-7 business days for any delayed adverse events.
Detailed description
Six male and/or female adult patients (greater than or equal to 18 years old), of any ethnicity and race, with unresectable stage III or stage IV cutaneous melanoma with accessible lesions, will be eligible for enrollment and treatment with IFx-Hu2.0. To be eligible for this study, patients with unresectable metastatic disease must have failed, refused or been deemed not candidates for at least one form of systemic anti-PD-1-based immunotherapy as well as BRAF inhibition, if BRAF V600 mutated. Talimogene laherparepvec (IMLYGIC®) is indicated for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Therefore, patients with unresectable cutaneous, subcutaneous, and nodal melanoma lesions recurrent after initial surgery must have failed, refused or been deemed not candidates for talimogene laherparepvec to be eligible for this study. Enrollees will receive IFx-Hu2.0 at a single time point. Depending on the number of accessible lesions, a patient could receive up to three doses across three lesions (one dose per lesion). Forty milliliters of peripheral blood will be collected from these patients prior to treatment administration and at the follow-up visit four weeks later. The target dose will be 100 μg of plasmid DNA per lesion injected at a final dose volume of 200 μL per lesion. To allow for the observation of any acute toxicity in the first subject enrolled and prevent any occurrence of excessive toxicities in subsequent subjects, the first subject enrolled will receive a single dose of IFx-Hu2.0. Subsequent subjects will be administered the product after at least seven days. Beyond the first subject, the maximum number of lesions to be injected at any given time point in the study phase proposed is three lesions. These samples will be used to perform complete blood counts (CBC) and clinical chemistry tests. A urine sample will be obtained for urinalysis for protein and blood at the same frequency. Blood samples will be drawn for immune response evaluation as well. At the end of the study period, a biopsy of the lesion injected and a non-injected lesion (if applicable) will be collected. If the patient has a response to therapy, the patient will have the option of continuing the study at three-week intervals so long as they have not progressed. Optional tumor biopsies and peripheral blood collections may be obtained on subsequent treatment cycles.
Interventions
BIOLOGICALIFx-Hu2.0
Subjects enrolled will receive a fixed IFx-Hu2.0 (plasmid DNA) dose of 0.1 mg injected in up to 3 lesions at a single time point (28-day follow-up post last injection).
Sponsors
H. Lee Moffitt Cancer Center and Research Institute
TuHURA Biosciences, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed unresectable stage III or stage IV malignant melanoma, with accessible cutaneous lesions * Must have measurable disease greater than 3 mm * At least one injectable lesion and one lesion for biopsy at study conclusion. Lymphocyte count ≥ 500,000 cells/mL * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Willing and able to give written, informed consent * If male or female of childbearing potential must be willing to use a contraceptive during the study and for six months afterward. A woman is considered to be of childbearing potential unless she has had a surgical procedure that would accomplish sterility such a bilateral tubal ligation, hysterectomy or has not had menses for the past 12 months. * Life expectancy greater than three months * To be eligible for this study, patients with unresectable metastatic disease must have failed, refused or been deemed not candidates for at least one form of systemic anti-PD-1-based immunotherapy as well as BRAF inhibition, if BRAF V600 mutated. * Patients with unresectable cutaneous, subcutaneous, and nodal melanoma lesions recurrent after initial surgery must have failed, refused or been deemed not candidates for talimogene laherparepvec to be eligible for this study. * The entry laboratory criteria for subject eligibility must be less than or equal to grade 1 adverse event levels for the parameters tested as defined by CTCAE v5.0.
Exclusion criteria
* Known brain metastases greater than 1 cm at screening. * Life expectancy of fewer than three months * Prior systemic anti-cancer treatment within three weeks from start of treatment (Day 0) * Current treatment with systemic immunosuppressive corticosteroid (greater than 10 mg of daily prednisone) doses or other immunosuppressants such as those needed for solid organ transplants. Medications needed to treat conditions such as reactive airway disease are not excluded. * Pregnant or lactating women * Presence of any uncontrolled and significant medical or psychiatric condition which would interfere with trial safety assessments * Treatment with any investigational product within the three weeks preceding injection * Immunizations for encapsulated bacteria were not given for patients who have undergone a splenectomy. * Serious underlying medical or psychiatric conditions, active infections requiring the use of antimicrobial drugs, or active bleeding that would make the subject unsuitable or unable to participate in the study * Concurrent chemotherapy or biological therapy. Concurrent radiotherapy is allowed as long as it is not the same site as the injected lesion. * Uncontrolled hepatitis B, hepatitis C, or HIV infection * History of organ allograft transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs) | 28 ± 7 Days | Safety was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Feasibility was defined as the ability to treat at least five of the six patients enrolled without drug-related dose-limiting toxicity (DLT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions. | 28 ± 7 days post treatment | Evaluation of response rate and assessment of the antitumor immune responses induced by IFx-Hu2.0 per RECIST v1.1 for target lesions. Complete Response (CR), Disappearance of all target lesions. Partial Response (PR), ≥ 30% decrease in the sum of the longest diameters of target lesions compared with baseline. Stable Disease (SD), Neither sufficient shrinkage to qualify for partial or complete response (CR or PR) nor sufficient increase to qualify for progressive disease (PD). Progressive Disease (PD), Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
Countries
United States
Participant flow
Recruitment details
This study had a goal of six evaluable patients. It was the intent of the study team to recruit an additional two patients to be screened and enrolled if any of the existing patients were lost to follow-up, withdrew consent, or exhibited disease progression.
Participants by arm
| Arm | Count |
|---|---|
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point Therapeutic Classification:
* Noncellular, Therapeutic Cancer Vaccine \> Immunomodulator
Route of Administration:
* Intratumoral injection of cutaneous, subcutaneous or nodal lesions
Mechanism of Action:
* Injection of the IFx-Hu2.0 plasmid DNA construct into the target lesion facilitates the localized expression of the highly immunogenic Emm55 protein by the tumor cells on their cell surface.
Physiological Effect:
* This expression then primes a cascade of immune events that exposes the patient-specific abnormal tumor antigens to the effector mechanisms of the immune system. The immune response becomes systemic as inter-antigenic epitope spreading produces neoantigens to naïve T cells. Therefore, injected lesions are targeted along with non-injected lesions (abscopal effect). This is especially important in conditions where the mutational phenotype varies greatly among individual lesions.
IFx-Hu2.0: Subjects enrolled will receive a fixed IFx-Hu2.0 (plasmid DNA) dose of 0.1 mg injected in up to 3 lesions at a single time point (28-day follow-up post last injection). | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| AJCC Clinical Staging Stage III | 1 Participants |
| AJCC Clinical Staging Stage III C | 4 Participants |
| AJCC Clinical Staging Stage IV | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 2 / 7 |
Outcome results
Primary
Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs)
Safety was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Feasibility was defined as the ability to treat at least five of the six patients enrolled without drug-related dose-limiting toxicity (DLT).
Time frame: 28 ± 7 Days
Population: The data analysis is described to assess the safety of the injection of the study agent in six patients the intention-to-treat (ITT) approach will be used for response to treatment data analysis of this trial (secondary objective).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs) | Participants Analyzed | 6 Participants |
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs) | Serious Adverse Events (SAEs) | 1 Participants |
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs) | Dose Limiting Toxicity (DLT) | 0 Participants |
Secondary
Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions.
Evaluation of response rate and assessment of the antitumor immune responses induced by IFx-Hu2.0 per RECIST v1.1 for target lesions. Complete Response (CR), Disappearance of all target lesions. Partial Response (PR), ≥ 30% decrease in the sum of the longest diameters of target lesions compared with baseline. Stable Disease (SD), Neither sufficient shrinkage to qualify for partial or complete response (CR or PR) nor sufficient increase to qualify for progressive disease (PD). Progressive Disease (PD), Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: 28 ± 7 days post treatment
Population: The intention-to-treat (ITT) approach will be used for response to treatment data analysis of this trial.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions. | Complete Response (CR) | 0 Participants |
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions. | Partial Response (PR) | 1 Participants |
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions. | Stable Disease (SD) | 2 Participants |
| IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point | Antitumor Response Induced by IFx-Hu2.0 Per RECIST v1.1 for Target Lesions. | Progressive Disease (PD) | 3 Participants |