Melanoma
Conditions
Keywords
Resectable Stage IIIB, IIIC, and IVM1a
Brief summary
This is a single-arm, open label, Phase II study evaluating the safety and efficacy of neoadjuvant Nivolumab and HF10 in resectable stage IIIB, IIIC, and IVM1a melanoma.
Interventions
DRUGNivolumab
Nivolumab at a dose of 240 mg given as an IV infusion starting on day 0. It will be given every 14 days for a total of 7 infusions; Then participant will undergo surgery. Nivolumab will then be administered at a flat dose of 480 mg IV every 28 days for up to one year.
DRUGHF10
1 x 107th TCID50/mL, intratumoral injection to a single or multiple eligible tumors for a total of 5 mL; on days 0, 7, 14, 21, 28, 42, 56, 70, 84 for a total of 9 injections. All eligible tumors except one will be treated with HF10 up to the maximum volume allowed. The untreated tumor will be used as an untreated control lesion.
Sponsors
Bristol-Myers Squibb
Takara Bio Inc.
University of Utah
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm, open label, Phase II
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must be \>18 years or older. * Participants must have stage IIIB, IIIC, or IVM1a (equivalent staging at time of enrollment via American Joint Committee on Cancer (AJCC) 7th edition) metastatic melanoma which is eligible for complete surgical resection. * Prior systemic, regional and radiation anticancer therapies must have been completed at least three months prior to enrollment. Prior therapies (including anti-programmed death (PD)-1 inhibitors) are allowed provided three months have elapsed from last dose. * Participants must be a candidate for intralesional therapy. * At least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion \> 10 mm in longest diameter OR * Multiple injectable melanoma lesions which in aggregate have a longest diameter of \> 10 mm AND * Must have no known bleeding diathesis or coagulopathy that would make intratumoral injection unsafe. * Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Serum (LDH) level \< 1.5 upper limit of normal (ULN) within 28 days prior to enrollment. * Participants have adequate organ function within 28 days prior to enrollment, as defined in the protocol * Men and women of childbearing potential must agree to use adequate contraception from the time of consent through 7 months after final nivolumab study treatment. * Females of childbearing potential must have a negative urine or serum pregnancy test within 1 week prior to the start of treatment. * Participants must be able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.
Exclusion criteria
* Participants with active visceral, central nervous system, or any bone metastases melanoma (Stage IVM1b or IVM1c). * Participants whose primary diagnosis was ocular melanoma. * Participants receiving anti-herpes medication (i.e., acyclovir, famciclovir, or valacyclovir) within 1 week prior to initiating HF10 treatment. Participants may not require intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug other than intermittent topical use. * Participants who have an active herpetic skin lesion(s) or prior complications of herpes simplex virus (HSV)-1 infection. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the investigator. * Medical history of autoimmune disease (e.g. Crohn's disease, ulcerative colitis) or other disease requiring systemic glucocorticoid or immunosuppressive therapy. Subjects who receive daily steroid replacement therapy serve as an exception to this rule. Daily prednisone equivalent at doses up to 10 mg would qualify. * Participants with clinically evident Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or Epstein-Barr Virus (EBV) infection are excluded. * Pregnant or breast feeding women; women desiring to become pregnant within the timeframe of the study are also excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Response | at time of surgery (12 weeks) | Following 12 weeks of neoadjuvant treatment with nivolumab and HF10, participants underwent definitive surgery. A percent viable tumor was assessed semi-quantitatively in the definitive surgical resection specimen by estimating the proportion of residual tumor in relation to the total tumor area and reported as percentage viability. A pathologic complete response was defined as no viable residual melanoma cells in the surgical specimen. A major pathologic response was defined as \<50% viable tumor cells. A minor pathologic response was defined as 50% or greater viable tumor cells, including specimens that had 100% viability at surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival: Number of Participants Alive One Year After Completing Adjuvant Nivolumab | up to 2 years post-surgery (1 year after end of adjuvant nivolumab, which was given for up to 1 year post-surgery) | Participants were followed for survival for one year after completion of adjuvant nivolumab. Adjuvant nivolumab was planned for up to one year of adjuvant treatment after surgery. This objective reports the number of participants who were alive one year after the completion of adjuvant nivolumab. |
| Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category | 12 weeks from baseline to surgery | Participants were assessed radiographically and clinically prior to study start and prior to surgery. Lesions were measured, and lesions that were at least 10 mm on CT, MRI, caliper, or ruler, or at least 20 mm on x-ray were documented as Target Lesions. Lesions that did not meet criteria to be Target Lesions were documented as Non-Target lesions. Measurements of Target Lesions were summed. Change in Target Lesion measurements was used to determine response by RECIST 1.1 criteria. Complete Response (CR) indicates a disappearance of all lesions. Partial Response (PR) indicates at least 30% decrease in the sum of Target Lesions. Progressive Disease (PD) indicates at least 20% increase in the sum of Target Lesions, or the appearance of one or more new lesions after baseline. Stable Disease (SD) is neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. Objective was reported as number of participants within each response category. |
| Recurrence-free Survival: Number of Participants With no Disease Recurrence After Surgery | up to 2 years post-surgery (1 year after end of adjuvant nivolumab, which was given for up to 1 year post-surgery) | Recurrence after surgery will be assessed by radiologic scans and confirmed by biopsy. Death within the follow-up period is also considered recurrence. This outcome will report the number of participants who were alive and who had no disease recurrence during the follow-up period. |
| Number of Participants With Adverse Events Related to HF10 Treatment | throughout HF10 treatment (up to 84 days) | Participants were monitored for adverse events (AEs) during treatment with HF10 using CTCAE v4 criteria. AEs were graded as being mild (grade 1), moderate (grade 2), grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal). Each adverse event was reviewed by a treating investigator for relatedness to study treatment. For this outcome, the number of participants who experienced any AEs that were possible, probably, or definitely related to HF10 treatment are grouped by grade 1-2 and grade 3-5 AEs. |
| Number of Participants With Adverse Events Related to Nivolumab Treatment | throughout nivolumab treatment (up to 84 days prior to surgery and up to 1 year after surgery) | Participants were monitored for adverse events (AEs) during treatment with nivolumab using CTCAE v4 criteria. AEs were graded as being mild (grade 1), moderate (grade 2), grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal). Each adverse event was reviewed by a treating investigator for relatedness to study treatment. For this outcome, the number of participants who experienced any AEs that were possible, probably, or definitely related to nivolumab treatment are grouped by grade 1-2 and grade 3-5 AEs. |
| Number of Participants With Complete Surgical Resection | Within 28 days after Day 84 | Participants' surgical samples were assessed by a pathologist after surgery to determine if complete surgical resection was achieved after neo-adjuvant treatment with nivolumab and HF10. R0 indicates a complete surgical resection was achieved and means no residual tumor was detected after after surgery. R1 means microscopic tumor was detected and a complete surgical resection was not achieved. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab and HF10 (All Participants ) Nivolumab: Nivolumab at a dose of 240 mg given as an IV infusion starting on day 0. It will be given every 14 days for a total of 7 infusions; Then participant will undergo surgery. Nivolumab will then be administered at a flat dose of 480 mg IV every 28 days for up to one year.
HF10: 1 x 107th TCID50/mL, intratumoral injection to a single or multiple eligible tumors for a total of 5 mL; on days 0, 7, 14, 21, 28, 42, 56, 70, 84 for a total of 9 injections. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease progression to an extent that didn't allow surgery | 1 |
Baseline characteristics
| Characteristic | Nivolumab and HF10 (All Participants ) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 71 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 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 | 1 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 | 6 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 6 Participants |
| Tumor Viability Percentage Tumor Viability < 90% | 0 Participants |
| Tumor Viability Percentage Tumor Viability >= 90% | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 |
Outcome results
Primary
Pathological Response
Following 12 weeks of neoadjuvant treatment with nivolumab and HF10, participants underwent definitive surgery. A percent viable tumor was assessed semi-quantitatively in the definitive surgical resection specimen by estimating the proportion of residual tumor in relation to the total tumor area and reported as percentage viability. A pathologic complete response was defined as no viable residual melanoma cells in the surgical specimen. A major pathologic response was defined as \<50% viable tumor cells. A minor pathologic response was defined as 50% or greater viable tumor cells, including specimens that had 100% viability at surgery.
Time frame: at time of surgery (12 weeks)
Population: One of seven participants had progressive disease while receiving neoadjuvant therapy and did not receive surgical resection and therefore per protocol was not assessed for response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nivolumab and HF10 (All Participants) | Pathological Response | Pathologic Complete Response (0% Tumor Viability) | 5 Participants |
| Nivolumab and HF10 (All Participants) | Pathological Response | Major Pathologic Response (<50% Tumor Viability) | 0 Participants |
| Nivolumab and HF10 (All Participants) | Pathological Response | Minor Pathologic Response (>=50% Tumor Viability) | 1 Participants |
Secondary
Number of Participants With Adverse Events Related to HF10 Treatment
Participants were monitored for adverse events (AEs) during treatment with HF10 using CTCAE v4 criteria. AEs were graded as being mild (grade 1), moderate (grade 2), grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal). Each adverse event was reviewed by a treating investigator for relatedness to study treatment. For this outcome, the number of participants who experienced any AEs that were possible, probably, or definitely related to HF10 treatment are grouped by grade 1-2 and grade 3-5 AEs.
Time frame: throughout HF10 treatment (up to 84 days)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nivolumab and HF10 (All Participants) | Number of Participants With Adverse Events Related to HF10 Treatment | Participants with G1-2 AEs related to HF10 | 7 Participants |
| Nivolumab and HF10 (All Participants) | Number of Participants With Adverse Events Related to HF10 Treatment | Participants with G3-5 AEs related to HF10 | 1 Participants |
Secondary
Number of Participants With Adverse Events Related to Nivolumab Treatment
Participants were monitored for adverse events (AEs) during treatment with nivolumab using CTCAE v4 criteria. AEs were graded as being mild (grade 1), moderate (grade 2), grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal). Each adverse event was reviewed by a treating investigator for relatedness to study treatment. For this outcome, the number of participants who experienced any AEs that were possible, probably, or definitely related to nivolumab treatment are grouped by grade 1-2 and grade 3-5 AEs.
Time frame: throughout nivolumab treatment (up to 84 days prior to surgery and up to 1 year after surgery)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nivolumab and HF10 (All Participants) | Number of Participants With Adverse Events Related to Nivolumab Treatment | Participants with G1-2 AEs related to Nivolumab | 7 Participants |
| Nivolumab and HF10 (All Participants) | Number of Participants With Adverse Events Related to Nivolumab Treatment | Participants with G3-5 AEs related to Nivolumab | 2 Participants |
Secondary
Number of Participants With Complete Surgical Resection
Participants' surgical samples were assessed by a pathologist after surgery to determine if complete surgical resection was achieved after neo-adjuvant treatment with nivolumab and HF10. R0 indicates a complete surgical resection was achieved and means no residual tumor was detected after after surgery. R1 means microscopic tumor was detected and a complete surgical resection was not achieved.
Time frame: Within 28 days after Day 84
Population: The participant who did not complete surgery was not followed for post-surgery outcomes.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nivolumab and HF10 (All Participants) | Number of Participants With Complete Surgical Resection | R0 Complete Surgical Resection | 5 Participants |
| Nivolumab and HF10 (All Participants) | Number of Participants With Complete Surgical Resection | R1 Incomplete Surgical Resection | 1 Participants |
Secondary
Overall Survival: Number of Participants Alive One Year After Completing Adjuvant Nivolumab
Participants were followed for survival for one year after completion of adjuvant nivolumab. Adjuvant nivolumab was planned for up to one year of adjuvant treatment after surgery. This objective reports the number of participants who were alive one year after the completion of adjuvant nivolumab.
Time frame: up to 2 years post-surgery (1 year after end of adjuvant nivolumab, which was given for up to 1 year post-surgery)
Population: The participant who did not complete surgery was not followed for post-surgery outcomes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab and HF10 (All Participants) | Overall Survival: Number of Participants Alive One Year After Completing Adjuvant Nivolumab | 5 Participants |
Secondary
Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category
Participants were assessed radiographically and clinically prior to study start and prior to surgery. Lesions were measured, and lesions that were at least 10 mm on CT, MRI, caliper, or ruler, or at least 20 mm on x-ray were documented as Target Lesions. Lesions that did not meet criteria to be Target Lesions were documented as Non-Target lesions. Measurements of Target Lesions were summed. Change in Target Lesion measurements was used to determine response by RECIST 1.1 criteria. Complete Response (CR) indicates a disappearance of all lesions. Partial Response (PR) indicates at least 30% decrease in the sum of Target Lesions. Progressive Disease (PD) indicates at least 20% increase in the sum of Target Lesions, or the appearance of one or more new lesions after baseline. Stable Disease (SD) is neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD. Objective was reported as number of participants within each response category.
Time frame: 12 weeks from baseline to surgery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nivolumab and HF10 (All Participants) | Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category | Progressive Disease (PD) | 3 Participants |
| Nivolumab and HF10 (All Participants) | Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category | Complete Response (CR) | 1 Participants |
| Nivolumab and HF10 (All Participants) | Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category | Partial Response (PR) | 0 Participants |
| Nivolumab and HF10 (All Participants) | Radiographic Response: Number of Participants Within Each Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Response Category | Stable Disease (SD) | 3 Participants |
Secondary
Recurrence-free Survival: Number of Participants With no Disease Recurrence After Surgery
Recurrence after surgery will be assessed by radiologic scans and confirmed by biopsy. Death within the follow-up period is also considered recurrence. This outcome will report the number of participants who were alive and who had no disease recurrence during the follow-up period.
Time frame: up to 2 years post-surgery (1 year after end of adjuvant nivolumab, which was given for up to 1 year post-surgery)
Population: The participant who did not complete surgery was not followed for post-surgery outcomes.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab and HF10 (All Participants) | Recurrence-free Survival: Number of Participants With no Disease Recurrence After Surgery | 2 Participants |