Melanoma
Conditions
Brief summary
The purpose of this study is to assess the safety and efficacy of the combination of IMM-101 with nivolumab.
Detailed description
This open-label study will assess the safety and efficacy of the combination of IMM-101 with nivolumab in patients with unresectable stage III, or stage IV melanoma who are either treatment-naive (cohort A) or whose disease has progressed during PD-1 blockade (cohort B). Ipilimumab may be used as a subsequent treatment in place of nivolumab alongside IMM-101 for patients in cohort B if their disease progresses on study. Eighteen patients will be enrolled into cohort A and 8 patients into cohort B.
Interventions
DRUGNivolumab
Nivolumab is to be administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information.
DRUGIpilimumab
Ipilimumab, when used as subsequent treatment for patients in cohort B, is to be administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information.
DRUGIMM-101
A single 0.1 mL intradermal injection of IMM 101 (10 mg/mL) given every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then one dose every 2 weeks for the next 3 doses. This is followed by a dose every 4 weeks thereafter.
Sponsors
Immodulon Therapeutics Ltd
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
Key Inclusion Criteria: 1. Histologically-confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma. 2. At least one measurable lesion by CT or MRI, according to RECIST 1.1. 3. Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) Performance Status of ≤1 at Day 0. 4. Known BRAF V600 mutation status or consent to BRAF V600 mutation testing during the Screening Period. 5. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration (Week 0, Visit 1). Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to enrolment (Week 0, Visit 1), and all related adverse events have resolved or stabilised. 6. Patient is considered suitable for treatment with nivolumab. For cohort A, the following key inclusion criteria apply: 1\. Patient is treatment-naive (i.e. no prior systemic anticancer therapy for unresectable or metastatic melanoma). For cohort B, the following key inclusion criteria apply: 1\. Patient is either currently receiving treatment with an anti-PD-1 therapy (monotherapy or in combination with ipilimumab), for advanced melanoma and has progressive disease by RECIST 1.1 after 4 or more doses; or has previously received at least 4 doses of PD-1 targeted therapy, alone or in combination with ipilimumab, had disease progression by RECIST 1.1 during this therapy and has not received any further therapy for advanced melanoma. Key
Exclusion criteria
1. Uveal/ocular melanoma. 2. Active brain metastases or leptomeningeal metastases. Patients with brain metastases are eligible for cohort B of the study only, if these have been treated and there is no MRI evidence of progression for at least 8 weeks after treatment is complete and within 21 days prior to first dose of study treatment administration. 3. Patient has documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents. 4. Patient has a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or immunosuppressant drugs (such as azathioprine, tacrolimus, cyclosporin) within the 14 days period before the first administration of IMM-101. For cohort A, patients meeting the following key criteria are also ineligible to participate in this study: 1\. Patient has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-PD ligand-1 (PD-L1), anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agent. For cohort B, patients meeting the following key criteria are also ineligible to participate in this study: 1\. Patient has received more than one treatment regimen for advanced (stage III/IV) disease prior to their anti PD-1 therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of the Combination of IMM-101 + Nivolumab | From the point of Informed Consent until end of the study assessment (up to 84 weeks) or until withdrawal from the study. | Incidence, frequency and severity of treatment emergent adverse events (TEAEs) throughout the study. |
| Overall Response Rate | From enrollment to end of study (18 months) or withdrawal, whichever was soonest | The primary endpoint of Overall Response Rate (ORR) is defined as the number of subjects with a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) divided by the number of subjects in the Intent-to-treat analysis set in each cohort of the study. The BOR will be determined once all the data up to and including the 12-month assessments for Cohort A or the 6-month assessment for Cohort B are available. It is defined as the best response designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response (BOR) Using RECIST 1.1 | 18 months | Best Overall Response (BOR) is defined as the best response (complete or partial response, stable disease or progressive disease) designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B).) Patients in cohort B who changed therapy without documented progression were censored at their last scan assessment prior to the change of therapy. |
| Progression Free Survival (PFS) | From Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). | Progression-free survival was defined as the time from Visit 1 (week 0) to the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). Progression was determined by the investigator using the CT or MRI scan or death due to any cause. Patients who died without reporting progression were considered to have progressed on the date of their death. Progression is defined by RECIST 1.1 guidelines as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. |
| Overall Survival (OS) | Overall survival was defined as the time from Visit 1 (week 0) until the end of the study (80 weeks) or until the date of death from any cause. | Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive. Post-study survival information was collected until database lock, for subjects completing or withdrawing from the study and included in the analysis. |
| Overall Survival (OS) at One Year | OS at 1 year was calculated after all patients had had the opportunity of 12 months treatment of study | Number of patients surviving at leat 12 months |
Countries
United Kingdom
Participant flow
Pre-assignment details
Twenty-two patients at 2 centres were consented and screened. Six patients failed to meet one or more of the specific inclusion criteria or met one or more exclusion criteria and were deemed screen failures.
Participants by arm
| Arm | Count |
|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) Patients in cohort A were given IMM-101 in combination with nivolumab. Patients in cohort B who fail to respond to treatment with IMM-101 and nivolumab, and who meet certain criteria, have the option to change treatment on study to IMM-101 and ipilimumab.
Nivolumab: Nivolumab is to be administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information.
Ipilimumab: Ipilimumab, when used as subsequent treatment for patients in cohort B, is to be administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information.
IMM-101: A single 0.1 mL intradermal injection of IMM 101 (10 mg/mL) given every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then one dose every 2 weeks for the next 3 doses. This is followed by a dose every 4 weeks thereafter. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Disease progression | 11 |
Baseline characteristics
| Characteristic | IMM-101 (and Nivolumab or Ipilimumab) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 68.5 years |
| PD-L1 status in Cohort A patients only PD-L1 Negative or Indeterminate | 4 participants |
| PD-L1 status in Cohort A patients only PD-L1 Positive | 6 participants |
| PD-L1 status in Cohort A patients only PD_L1 status Not Assessed or Unknown | 1 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 | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United Kingdom | 16 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 16 | 1 / 1 |
| other Total, other adverse events | 16 / 16 | 1 / 1 |
| serious Total, serious adverse events | 12 / 16 | 1 / 1 |
Outcome results
Primary
Overall Response Rate
The primary endpoint of Overall Response Rate (ORR) is defined as the number of subjects with a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) divided by the number of subjects in the Intent-to-treat analysis set in each cohort of the study. The BOR will be determined once all the data up to and including the 12-month assessments for Cohort A or the 6-month assessment for Cohort B are available. It is defined as the best response designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B).
Time frame: From enrollment to end of study (18 months) or withdrawal, whichever was soonest
Population: Intent-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Response Rate | 8 Participants |
| Cohort B | Overall Response Rate | 0 Participants |
Primary
Safety and Tolerability of the Combination of IMM-101 + Nivolumab
Incidence, frequency and severity of treatment emergent adverse events (TEAEs) throughout the study.
Time frame: From the point of Informed Consent until end of the study assessment (up to 84 weeks) or until withdrawal from the study.
Population: The Safety Analysis Set (SAF) included all patients who received at least one dose of IMM-101, irrespective of compliance with eligibility and other protocol criteria.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Treatment emergent adverse events (TEAEs) | 16 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Treatment-related TEAEs | 14 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Serious TEAEs | 6 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Immune relared TEAEs | 14 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | TEAEs leading to discontinuation of IMM-101 | 3 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | TEAEs leading to withdrawal | 1 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | TEAEs leading to death | 0 Participants |
Secondary
Best Overall Response (BOR) Using RECIST 1.1
Best Overall Response (BOR) is defined as the best response (complete or partial response, stable disease or progressive disease) designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B).) Patients in cohort B who changed therapy without documented progression were censored at their last scan assessment prior to the change of therapy.
Time frame: 18 months
Population: Intent to treat population - all patients who received at least one dose of IMM-101
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Best Overall Response (BOR) Using RECIST 1.1 | Complete Response (CR) | 2 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Best Overall Response (BOR) Using RECIST 1.1 | Partial Response (PR) | 6 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Best Overall Response (BOR) Using RECIST 1.1 | Stable Disease | 1 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Best Overall Response (BOR) Using RECIST 1.1 | Disease Progression | 2 Participants |
| Cohort B | Best Overall Response (BOR) Using RECIST 1.1 | Disease Progression | 5 Participants |
| Cohort B | Best Overall Response (BOR) Using RECIST 1.1 | Complete Response (CR) | 0 Participants |
| Cohort B | Best Overall Response (BOR) Using RECIST 1.1 | Stable Disease | 0 Participants |
| Cohort B | Best Overall Response (BOR) Using RECIST 1.1 | Partial Response (PR) | 0 Participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive. Post-study survival information was collected until database lock, for subjects completing or withdrawing from the study and included in the analysis.
Time frame: Overall survival was defined as the time from Visit 1 (week 0) until the end of the study (80 weeks) or until the date of death from any cause.
Population: Intent-to-treat
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | >3 months but < or = to 6 months | 0 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | >9 months but < or = to 12 months | 0 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | < or = to 3 months | 1 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | >12 months but < or = to 18 months | 0 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | >18 months | 9 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) | >6 months but < or = to 9 months | 1 Participants |
| Cohort B | Overall Survival (OS) | >18 months | 0 Participants |
| Cohort B | Overall Survival (OS) | < or = to 3 months | 0 Participants |
| Cohort B | Overall Survival (OS) | >3 months but < or = to 6 months | 0 Participants |
| Cohort B | Overall Survival (OS) | >6 months but < or = to 9 months | 2 Participants |
| Cohort B | Overall Survival (OS) | >9 months but < or = to 12 months | 2 Participants |
| Cohort B | Overall Survival (OS) | >12 months but < or = to 18 months | 1 Participants |
Secondary
Overall Survival (OS) at One Year
Number of patients surviving at leat 12 months
Time frame: OS at 1 year was calculated after all patients had had the opportunity of 12 months treatment of study
Population: Intent-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Overall Survival (OS) at One Year | 9 Participants |
| Cohort B | Overall Survival (OS) at One Year | 1 Participants |
Secondary
Progression Free Survival (PFS)
Progression-free survival was defined as the time from Visit 1 (week 0) to the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). Progression was determined by the investigator using the CT or MRI scan or death due to any cause. Patients who died without reporting progression were considered to have progressed on the date of their death. Progression is defined by RECIST 1.1 guidelines as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time frame: From Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first).
Population: Intent-to-treat
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | Less than or equal to 3 months | 2 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | >3 months but < or = to 6 months | 1 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | >6 months but < or = to 9 months | 3 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | >9 months but < or = to 12 months | 1 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | >12 months but < or = to 18 months | 0 Participants |
| IMM-101 (and Nivolumab or Ipilimumab) | Progression Free Survival (PFS) | .18 months | 4 Participants |
| Cohort B | Progression Free Survival (PFS) | >12 months but < or = to 18 months | 0 Participants |
| Cohort B | Progression Free Survival (PFS) | Less than or equal to 3 months | 4 Participants |
| Cohort B | Progression Free Survival (PFS) | >9 months but < or = to 12 months | 0 Participants |
| Cohort B | Progression Free Survival (PFS) | >3 months but < or = to 6 months | 1 Participants |
| Cohort B | Progression Free Survival (PFS) | .18 months | 0 Participants |
| Cohort B | Progression Free Survival (PFS) | >6 months but < or = to 9 months | 0 Participants |