Melanoma, Skin Cancer
Conditions
Keywords
Stage III Melanoma, Stage IV Melanoma, HDAC Inhibitor
Brief summary
The purpose of this study is to find out if an investigational drug called panobinostat can be given safely with another drug called ipilimumab. Investigators want to learn more about the side effects of this combination of drugs using different doses of panobinostat and the same dose of ipilimumab.
Interventions
DRUGPanobinostat
Participants will be assigned to receive a certain dose of panobinostat (5, 10, 15, or 20 mg). The dose of panobinostat will depend on the time point the participant enters the study and the side effects of other participants already on the study.
DRUGIpilimumab
Dose of ipilimumab of 3 mg per kg (mg/kg) of body weight.
Sponsors
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women ≥ 18 years old * Participants must be ipilimumab naïve with progressive unresectable Stage III or Stage IV melanoma who are either treatment naïve or may have been treated with up to 3 prior treatments for melanoma (e.g., chemotherapy, biologic or targeted therapy or IL-2). * Histologic or cytologic confirmation of stage III or stage IV melanoma * Measurable disease at baseline as assessed by CT and/or MRI * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Screening laboratory values must meet the following criteria: white blood count (WBCs) ≥ 2000/μL; Neutrophils ≥ 1500/μL; Platelets ≥ 100 x 10\^3/μL; Hemoglobin ≥ 9.0 g/dL; Creatinine Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance \> 40 mL/minute (using Cockcroft/Gault formula); aspartic transaminase (AST) ≤ 3 x ULN; alanine transaminase (ALT) ≤ 3 x ULN; Total Bilirubin ≤ 1.5 x ULN (except those with Gilbert Syndrome who must have total bilirubin \< 3.0 mg/dL) * Men and women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Women must have a negative serum pregnancy test within 72 hours prior to the start of investigational product.
Exclusion criteria
* Known or suspected brain metastasis, or brain as the only site of disease, with the following exceptions: controlled brain metastasis (no radiographic progression at least 4 weeks following radiation and/or surgical treatment, off steroids for at least 4 weeks, and have no new or progressing neurological signs or symptoms); history of prior malignancy with the exception of carcinoma in situ of the cervix or other malignancy diagnosed \> 2 years ago that has undergone potentially curative therapy with no evidence of disease for the last ≥ 2 years and that is deemed by the investigator to be at a low risk of recurrence * Active autoimmune disease or a history of known or suspected autoimmune disease with the exception of subjects with isolated vitiligo, treated thyroiditis or resolved childhood asthma/atopy * Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C infection * History of any hepatitis (e.g., alcohol or non-alcohol steatohepatitis (NASH), drug- related, autoimmune) * Evidence of active infection that requires anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to initiation of study drug therapy * History of acute diverticulitis, or current chronic diarrhea * Active peptic ulcer disease even if asymptomatic * History of adrenal insufficiency (including subjects using replacement therapy) * Prior organ allograft or allogeneic bone marrow transplantation * Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: Myocardial infarction within the past 6 months; Uncontrolled angina within the past 6 months; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsades de pointes). Controlled atrial fibrillation by itself is not an exclusion criterion.; Baseline corrected QT interval (QTc) interval greater than 500 milliseconds * Baseline toxicities from prior anti-cancer treatments \> Grade 1 * Inability to be venipunctured and/or tolerate venous access * Any major surgery within 4 weeks or a diagnostic procedure (e.g. incision, needle biopsy) within 1 day of study drug administration * Any current or recent (within 3 months) gastrointestinal disease that could potentially impact the ability to swallow and/or absorb study drug (i.e., gastrointestinal surgery, malabsorption syndrome) * Diabetes mellitus uncontrolled by medication * Known drug or alcohol abuse * Presence of underlying medical condition that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of panobinostat and ipilimumab in treated subjects * History of allergy to components of ipilimumab or panobinostat, or known allergy to other antibody therapies. * WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of pregnancy for the entire study period and for at least 12 weeks after the last dose of investigational product * Women who are pregnant or breastfeeding * Women with a positive pregnancy test on enrollment or prior to investigational product administration * Sexually active fertile men not using effective birth control if their partners are WOCBP * Exposure to any investigational drug within 4 weeks of study drug administration. * Any anti-cancer therapy (e.g., chemotherapy, biologics, radiotherapy, or hormonal treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration * Prior therapy with an anti-CTLA4 antibody or an HDAC inhibitor * Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation therapy, standard or investigational * Prisoners or subjects who are involuntarily incarcerated * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Up to 36 months | MTD and recommended Phase 2 dose (RP2D) of panobinostat (PAN), administered in combination with ipilimumab (IPI) in participants with unresectable Stage III or Stage IV melanoma. The goal is to enroll up to 36 patients for determination of the MTD, but will be successfully concluded earlier if 12 patients are accrued at the dose determined to be the MTD, with 3 dose limiting toxicities (DLTs). All participants who receive study any drug therapy will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Triplicate 12-lead electrocardiograms (ECGs) will be collected prior to dosing on Day 1 of induction cycle 1. MTD of PAN in milligrams (mg), with IPI at 3 mg/kg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immune Related Overall Response Rate (ORR) | Up to 36 months | Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related Response Criteria (irRC). RECIST: Best overall response from start of treatment until disease progression/recurrence. Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from date of documentation of irCR. Immune-related Partial Response (irPR): Sum of the products of the 2 largest perpendicular diameters of all index lesions, measured and captured as the Sum of Product of Diameters (SPD) baseline. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Immune-related Progressive Disease (irPD): At least a 25% increase in the SPD of all index lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the index lesions. |
| Progression Free Survival (PFS) | Up to 6 months | Progression Free Survival (PFS): is defined for each participant as the time from first dosing to the first observation of disease progression or death due to any cause. If a subject has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. PFS will be calculated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions. |
| Overall Survival (OS) | 36 months | Overall survival: The time from randomization until death from any cause. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center, November 2014 through November 2016.
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat 5 mg Participants who received 5 mg of Panobinostat along with 3 mg Ipililumab | 6 |
| Panobinostat 10 mg Participants who received 10 mg of Panobinostat along with 3 mg Ipililumab | 11 |
| Total | 17 |
Baseline characteristics
| Characteristic | Panobinostat 5 mg | Total | Panobinostat 10 mg |
|---|---|---|---|
| Age, Continuous | 64 years | 66 years | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 16 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 17 Participants | 11 Participants |
| Region of Enrollment United States | 6 participants | 17 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 13 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 0 / 11 |
| other Total, other adverse events | 6 / 6 | 11 / 11 |
| serious Total, serious adverse events | 4 / 6 | 7 / 11 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
MTD and recommended Phase 2 dose (RP2D) of panobinostat (PAN), administered in combination with ipilimumab (IPI) in participants with unresectable Stage III or Stage IV melanoma. The goal is to enroll up to 36 patients for determination of the MTD, but will be successfully concluded earlier if 12 patients are accrued at the dose determined to be the MTD, with 3 dose limiting toxicities (DLTs). All participants who receive study any drug therapy will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Triplicate 12-lead electrocardiograms (ECGs) will be collected prior to dosing on Day 1 of induction cycle 1. MTD of PAN in milligrams (mg), with IPI at 3 mg/kg.
Time frame: Up to 36 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation of Panobinostat, Plus Ipilimumab | Maximum Tolerated Dose (MTD) | 5 mg |
Secondary
Immune Related Overall Response Rate (ORR)
Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related Response Criteria (irRC). RECIST: Best overall response from start of treatment until disease progression/recurrence. Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from date of documentation of irCR. Immune-related Partial Response (irPR): Sum of the products of the 2 largest perpendicular diameters of all index lesions, measured and captured as the Sum of Product of Diameters (SPD) baseline. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Immune-related Progressive Disease (irPD): At least a 25% increase in the SPD of all index lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the index lesions.
Time frame: Up to 36 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation of Panobinostat, Plus Ipilimumab | Immune Related Overall Response Rate (ORR) | Partial Response | 1 Participants |
| Dose Escalation of Panobinostat, Plus Ipilimumab | Immune Related Overall Response Rate (ORR) | Complete Response | 0 Participants |
| Dose Escalation of Panobinostat, Plus Ipilimumab | Immune Related Overall Response Rate (ORR) | Stable Disease | 3 Participants |
| Panobinostat 10 mg | Immune Related Overall Response Rate (ORR) | Complete Response | 0 Participants |
| Panobinostat 10 mg | Immune Related Overall Response Rate (ORR) | Stable Disease | 3 Participants |
| Panobinostat 10 mg | Immune Related Overall Response Rate (ORR) | Partial Response | 1 Participants |
Secondary
Overall Survival (OS)
Overall survival: The time from randomization until death from any cause.
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation of Panobinostat, Plus Ipilimumab | Overall Survival (OS) | 25.91 Months |
| Panobinostat 10 mg | Overall Survival (OS) | 12 Months |
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS): is defined for each participant as the time from first dosing to the first observation of disease progression or death due to any cause. If a subject has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. PFS will be calculated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions.
Time frame: Up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation of Panobinostat, Plus Ipilimumab | Progression Free Survival (PFS) | 4.19 Months |
| Panobinostat 10 mg | Progression Free Survival (PFS) | 1.81 Months |