Melanoma
Conditions
Keywords
Ipilimumab, Nivolumab, Stage III-IV Melanoma, Progressed or Relapsed on PD-1 Inhibitor Therapy, 16-043
Brief summary
The purpose of this research study is to learn whether patients whose disease grows after being treated with nivolumab or pembrolizumab respond to ipilimumab (Yervoy®) alone or in combination with nivolumab (Opdivo®).
Interventions
DRUGipilimumab
DRUGnivolumab
Sponsors
Bristol-Myers Squibb
Parker Institute for Cancer Immunotherapy
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. American Joint Committee on Cancer (AJCC) (2009) Stage IV cutaneous melanoma or Stage III cutaneous, acral or mucosal melanoma that is judged inoperable. Patients with a history of uveal melanoma are not eligible. 2. Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with computerized tomography (CT) scan. Patients must have at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) and a separate lesion amenable to biopsy. 3. Histologic proof of melanoma reviewed and confirmed by the enrolling site. 4. Previous treatment with a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor with documented progression of disease on most recent CT scan. Progression of disease is defined as 1) the appearance of a new measureable lesion (\>10 mm) on cross-sectional imaging or physical examination OR 2) enlargement of previously detected lesions on two consecutive imaging studies OR 3) enlargement of a previously detected lesion with correlative symptomatology on one cross-sectional imaging study. Patients remain eligible if they had a previous response to a PD-1 inhibitor, including patients who had a complete response, partial response or stable disease (SD). Primary progressing patients are defined as those who received anti-PD-1 therapy within 2 months of study enrollment. Patients with relapsed disease are defined as those who received their last dose of PD-1 blocking antibody ≥2 months prior to enrollment. 5. Patients who received adjuvant PD-1 therapy who then develop measurable disease are eligible. However, they must have received their last dose of PD-1/PD-L1 blockade within two months of enrollment in this study. They will be stratified with patients who have primary progressive disease. 6. Life expectancy of greater than 3 months. 7. Age ≥ 18 years old. 8. Eastern Cooperative Oncology Group performance status = 0 or 1 or Karnofsky Performance Status equivalent. 9. Patients must have adequate organ and marrow function as defined below: 1. White blood cells \>2, 000/microliter (mcL) 2. Absolute neutrophil count \>1,500/mcL 3. Platelets \>100,000/mcL 4. Hemoglobin \> 9.0 g/dL 5. Total bilirubin ≤ 1.5 X institution's upper limit of normal 6. Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 X institution's upper limit of normal for patients with no concurrent liver metastases, OR ≤ 5 X institution's upper limit of normal for patients with concurrent liver metastases 7. Serum creatinine \< 1.5x OR creatinine clearance of at least 40 10. Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to the start of study drug. A woman of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 50 in the absence of other biologic or physiologic causes. 11. Women with child bearing potential and men with reproductive potential must be willing to practice acceptable methods of contraception. 12. Ability to understand and the willingness to sign a written informed consent document. 13. Willingness to undergo biopsy of metastatic site or site of unresectable disease prior to randomization. Main
Exclusion criteria
1. History of another malignancy except for those who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies not requiring active therapy, are eligible. Consult the study Medical Monitor if unsure whether second malignancies meet the requirements specified above. 2. Any major surgical procedures or external beam radiotherapy within 14 days prior to study drug administration. 3. Use of other investigational drugs within 28 days prior to study drug administration. 4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases must have been stable for at least 1 month and require treatment with less than 10mg/day prednisone equivalent for at least 2 weeks prior to study drug administration. 5. Prior exposure to either ipilimumab or combined checkpoint blockade. 6. Any diagnosis of autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, adrenal insufficiency on replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 7. Pregnant women and lactating women. 8. History of uveal melanoma. 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV or HCV infection, which will be allowed). Once-documented negative result for HIV, HBV, and HCV is sufficient. 10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and psychiatric illness/social situations that would limit compliance with study requirements. 11. Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted. 12. Patients with history of any grade 4 toxicity during previous anti PD-1 treatment or history of Grade 3 or higher pneumonitis. 13. Patients with a history of Grade ≥2 neuropathy. 14. Prisoners or patients who are involuntarily incarcerated. 15. Children under the age of 18. 16. Patients who require hemodialysis. 17. Patients with a history of allergy to study drug components or history of a severe hypersensitivity reaction to any monoclonal antibody.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18 | Week 18 | Overall Response Rate was defined as any participant who had a Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1 by week 18 of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Status at Week 18 | Week 18 | Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 18. |
| Time to Treatment Failure (TTF) | The time from treatment initiation until a subsequent therapy is started or death. | Time to Treatment Failure is defined as the time from treatment initiation until the participant starts a subsequent therapy or death, whichever comes first. |
| Overall Survival (OS) | Death | Overall Survival is defined as the time of treatment initiation to death by any cause |
| Number of Participants With Grade 3 or 4 Adverse Events | AE were monitored during each treatment cycle and could be reported until 30 days after the last dose of study treatment had been administered. | The occurrence of Grade 3 and Grade 4 adverse events (AE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
| Disease Control Rate (DCR) Status at Week 12 | Week 12 | Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 12. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at four institutions in the United States. Recruitment occurred between June 2016 to May 2018.
Pre-assignment details
33 participants were assessed for eligibility. Out of the 33 participants, 20 patients met the inclusion/exclusion criteria and were randomized to the study arms.
Participants by arm
| Arm | Count |
|---|---|
| Ipilimumab and Nivolumab For patients in the combination arm, nivolumab will first be administered intravenously at a dose of 1 mg/kg of body weight over a period of 60 minutes, once every 3 weeks for four doses. Thirty minutes after the completion of each nivolumab infusion, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes.
ipilimumab
nivolumab | 10 |
| Ipilimumab In the ipilimumab monotherapy group, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes once every 3 weeks for four doses.
ipilimumab | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Study terminated by Sponsor | 6 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ipilimumab and Nivolumab | Total | Ipilimumab |
|---|---|---|---|
| Age, Continuous | 66 years | 60 years | 56 years |
| Best response to prior anti-PD-1 treatment Progressive Disease | 9 Participants | 15 Participants | 6 Participants |
| Best response to prior anti-PD-1 treatment Stable Disease | 0 Participants | 1 Participants | 1 Participants |
| Best response to prior anti-PD-1 treatment Unknown | 1 Participants | 3 Participants | 2 Participants |
| ECOG Performance Status ECOG Score = 0 | 7 Participants | 13 Participants | 6 Participants |
| ECOG Performance Status ECOG Score = 1 | 3 Participants | 6 Participants | 3 Participants |
| Genomic Driver Neuroblastoma RAS viral oncogene homolog (NRAS) | 2 Participants | 6 Participants | 4 Participants |
| Genomic Driver Other/Unknown | 5 Participants | 8 Participants | 3 Participants |
| Genomic Driver v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) | 3 Participants | 5 Participants | 2 Participants |
| Median lactate dehydrogenase | 214 units/L | 211 units/L | 208 units/L |
| Median time since last anti-PD-1 treatment | 4.3 weeks | 5.1 weeks | 6.0 weeks |
| M stage M0 | 1 Participants | 4 Participants | 3 Participants |
| M stage M1a | 2 Participants | 3 Participants | 1 Participants |
| M stage M1b | 3 Participants | 5 Participants | 2 Participants |
| M stage M1c - without brain metastases | 4 Participants | 7 Participants | 3 Participants |
| Prior Treatment Anti-PD-1 | 10 Participants | 19 Participants | 9 Participants |
| Prior Treatment Other | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 16 Participants | 9 Participants |
| Region of Enrollment United States | 10 participants | 19 participants | 9 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 15 Participants | 6 Participants |
| Type of Melanoma Acral | 1 Participants | 2 Participants | 1 Participants |
| Type of Melanoma Cutaneous | 8 Participants | 15 Participants | 7 Participants |
| Type of Melanoma Mucosal | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 10 | 1 / 9 |
| other Total, other adverse events | 10 / 10 | 9 / 9 |
| serious Total, serious adverse events | 2 / 10 | 4 / 9 |
Outcome results
Primary
Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18
Overall Response Rate was defined as any participant who had a Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1 by week 18 of treatment.
Time frame: Week 18
Population: Efficacy-Evaluable Population. The efficacy-evaluable population includes all participants who were randomly allocated to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this population, participant treatment groups are defined according to the treatment that was assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab and Nivolumab | Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18 | 20 percentage of participants |
| Ipilimumab | Overall Response Rate (ORR) as Defined by RECIST v1.1 at Week 18 | 56 percentage of participants |
Secondary
Disease Control Rate (DCR) Status at Week 12
Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 12.
Time frame: Week 12
Population: Efficacy-Evaluable Population. The efficacy-evaluable population includes all participants who were randomly allocated to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this population, participant treatment groups are defined according to the treatment that was assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab and Nivolumab | Disease Control Rate (DCR) Status at Week 12 | 60.0 Percentage of participants |
| Ipilimumab | Disease Control Rate (DCR) Status at Week 12 | 55.6 Percentage of participants |
Secondary
Disease Control Rate (DCR) Status at Week 18
Disease Control Rate was defined as any participant who achieved a complete response (CR), partial response (PR), or who remained stable (SD) as defined in Recist v1.1 at week 18.
Time frame: Week 18
Population: Efficacy-Evaluable Population. The efficacy-evaluable population includes all participants who were randomly allocated to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this population, participant treatment groups are defined according to the treatment that was assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ipilimumab and Nivolumab | Disease Control Rate (DCR) Status at Week 18 | 60 percentage of participants |
| Ipilimumab | Disease Control Rate (DCR) Status at Week 18 | 67 percentage of participants |
Secondary
Number of Participants With Grade 3 or 4 Adverse Events
The occurrence of Grade 3 and Grade 4 adverse events (AE) assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: AE were monitored during each treatment cycle and could be reported until 30 days after the last dose of study treatment had been administered.
Population: Safety-Evaluable Population. The safety-evaluable population includes all participants who received at least one dose of any study intervention. For analyses based on this population, participant treatment groups will be defined according to the treatment that was assigned at randomization. However, if a participant received the incorrect study drug for the entire period of treatment, the participant's treatment group will be defined as the treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ipilimumab and Nivolumab | Number of Participants With Grade 3 or 4 Adverse Events | 4 Participants |
| Ipilimumab | Number of Participants With Grade 3 or 4 Adverse Events | 5 Participants |
Secondary
Overall Survival (OS)
Overall Survival is defined as the time of treatment initiation to death by any cause
Time frame: Death
Population: Efficacy-Evaluable Population. The efficacy-evaluable population includes all participants who were randomly allocated to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this population, participant treatment groups are defined according to the treatment that was assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ipilimumab and Nivolumab | Overall Survival (OS) | 2 Participants |
| Ipilimumab | Overall Survival (OS) | 1 Participants |
Secondary
Time to Treatment Failure (TTF)
Time to Treatment Failure is defined as the time from treatment initiation until the participant starts a subsequent therapy or death, whichever comes first.
Time frame: The time from treatment initiation until a subsequent therapy is started or death.
Population: Efficacy-Evaluable Population. The efficacy-evaluable population includes all participants who were randomly allocated to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this population, participant treatment groups are defined according to the treatment that was assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab and Nivolumab | Time to Treatment Failure (TTF) | 26.9 months |
| Ipilimumab | Time to Treatment Failure (TTF) | 13.6 months |