Stage IV Melanoma
Conditions
Brief summary
Primary: * Phase Ib: To define the safety, tolerability and maximum tolerated dose (MTD) of lenvatinib administered in combination with dacarbazine. * Phase II: To evaluate the safety and tolerability of lenvatinib administered in combination with dacarbazine, compared with dacarbazine alone. Secondary: -Phase II: To make a preliminary assessment of the efficacy of lenvatinib administered in combination with dacarbazine, compared with dacarbazine alone.
Detailed description
Safety was assessed by monitoring and recording all treatment emergent adverse events (AEs) and serious adverse events (SAEs); regular monitoring of clinical laboratory parameters; periodic measurement of vital signs and electrocardiograms (ECGs); dose limiting toxicities; performance of physical examinations; concomitant medications and procedures.
Interventions
DRUGLenvatinib
Lenvatinib tablets administered orally at doses of 16 mg, 20 mg, or 22 mg, once daily continuously over 3 weeks (21 days) during each 21-day cycle
DRUGDacarbazine
Dacarbazine (1000 mg/m2) infusion over 60 minutes on Day 1 of each 21-day cycle.
Sponsors
Quintiles, Inc.
Eisai Inc.
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
1. Patients with histologically-confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer (AJCC)). 2. No prior cytokine, chemotherapy, or targeted therapy for Stage IV melanoma. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 4. Life expectancy greater than or equal to 3 months. 5. At least 1 site of measurable disease by RECIST 1.1. 6. Adequate hematologic, renal, liver, and coagulation system function as defined by laboratory values performed within 21 days prior to initiation of dosing. 7. Blood pressure must be well-controlled (less than or equal to 140/90 mmHg at screening) with or without antihypertensive medication. Patients must have no history of hypertensive crisis or hypertensive encephalopathy.
Exclusion criteria
1. Known central nervous system (CNS) lesions, except for asymptomatic, nonprogressive, treated brain metastases. Treatment for brain metastases must have been completed at least 4 weeks prior to Day 1 and may include whole brain radiotherapy (WBRT), radiosurgery \[RS; Gamma Knife, linear accelerator (LINAC), or equivalent\] or a combination as deemed appropriate by the treating physician. Dexamethasone must be discontinued at least 3 weeks prior to Day 1. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. 2. Lactate dehydrogenase greater than or equal to 2.0 x upper limit of normal (ULN). 3. Subjects with proteinuria greater than 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour urine protein greater than or equal to 1 g/24 hours will be ineligible. 4. Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives or avoidance of pregnancy measures. 5. Other active malignancy. 6. History of or known carcinomatous meningitis. 7. History of or known ocular melanoma. 8. Are currently receiving any other treatment for the tumor (including palliative radiotherapy) aside from control of symptoms. 9. Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to grade less than or equal to 1, except for alopecia. 10. Received radiotherapy within the 30 days prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to grade less than or equal to 1, except for alopecia. 11. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment. Minor surgery such as Portacath placement or skin biopsy is permitted if greater than or equal to 7 days have passed. 12. History of bleeding diathesis or coagulopathy. 13. Current use of anti-coagulants such as Vitamin K antagonists, unfractionated heparin, or low molecular weight heparin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | From Day 1 through 21 days (one cycle) | DLTs were defined as clinically significant adverse events (AEs) occurring less than or equal to 21 days after commencing study treatment and considered by the Investigator to be possibly or probably related to study treatment. |
| Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | From signing of informed consent up to 30 days after the last dose, up to approximately 2 years | Safety assessments consisted of monitoring and recording all AEs, including all Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) grades, and SAEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. Details of AEs and SAEs are provided in the reported adverse event section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) (for Phase 2) | From the date of randomization until the date of disease progression or death (whichever was earlier) or up to approximately 2 years | PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression of such participant's disease based on Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST v. 1.1) or (2) the date of such participant's death due to any cause. Progression was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions, based on Investigator assessment according to RECIST 1.1. If missing assessments, imputed dates were used in the analysis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) (for Phase 2) | From the date of randomization until disease progression or death or up to approximately 2 years | TTP, defined as the time from the date of randomization until the date of progressive disease. |
| Overall Survival (OS) (for Phase 2) | From the date of randomization until death or up to approximately 2 years | OS, defined as the time from the date of randomization until the date of death. Few events of deaths (9 events in the Lenvatinib + Dacarbazine arm and 4 events in the Dacarbazine arm) were reported to calculate the median OS or to draw conclusions regarding the OS. |
| Overall Response Rate (ORR) (for Phase 2) | From the date of randomization until disease progression or death or up to approximately 2 years | ORR, defined as percentage of participants with best confirmed response (complete response \[CR\] or partial response \[PR\]). A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded. |
Countries
Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 16 participants were enrolled in the Phase 1b portion of the study; all 16 participants received study treatment. A total of 82 participants were randomized in the Phase 2 portion of the study and a total of 81 participants received treatment. In the Darcarbazine arm, one participant withdrew consent prior to receiving study treatment.
Participants by arm
| Arm | Count |
|---|---|
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) Participants received 16 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit | 3 |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit | 7 |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) Participants received 22 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit | 6 |
| 20 mg Lenvatinib + Dacarbazine (Phase 2) Participants received 20 mg lenvatinib once daily continuously over 3 weeks (21 days) during each cycle in combination with dacarbazine (1000 mg/m2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit | 42 |
| Dacarbazine (Phase 2) Participants received dacarbazine (1000 mg/m2) on Day 1 of each 21-day cycle upto eight 21-day cycles (24 weeks) or more if participants experience clinical benefit | 39 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 1 | 1 | 1 | 7 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 2 | 1 |
| Overall Study | Started a New Line of Therapy | 2 | 6 | 4 | 25 | 33 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 5 | 1 |
Baseline characteristics
| Characteristic | 22 mg Lenvatinib + Dacarbazine (Phase 1b) | 16 mg Lenvatinib + Dacarbazine (Phase 1b) | 20 mg Lenvatinib + Dacarbazine (Phase 1b) | 20 mg Lenvatinib + Dacarbazine (Phase 2) | Dacarbazine (Phase 2) | Total |
|---|---|---|---|---|---|---|
| Age, Customized 18 years and older | 6 Participants | 3 Participants | 7 Participants | 42 Participants | 39 Participants | 97 Participants |
| Sex/Gender, Customized Female | 2 participants | 0 participants | 5 participants | 17 participants | 16 participants | 40 participants |
| Sex/Gender, Customized Male | 4 participants | 3 participants | 2 participants | 25 participants | 23 participants | 57 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 6 / 6 | 40 / 42 | 31 / 39 |
| serious Total, serious adverse events | 2 / 3 | 4 / 7 | 2 / 6 | 16 / 42 | 1 / 39 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b)
DLTs were defined as clinically significant adverse events (AEs) occurring less than or equal to 21 days after commencing study treatment and considered by the Investigator to be possibly or probably related to study treatment.
Time frame: From Day 1 through 21 days (one cycle)
Population: Safety Analysis Set: All participants enrolled in the Phase 1b portion of this study, except for those who (i) dropped out of the study prior to receiving any study drug, or (ii) were without any safety assessment following the first dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 febrile neutropenia | 0 Participants with DLT |
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Participants with DLTs | 0 Participants with DLT |
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 thrombocytopenia | 0 Participants with DLT |
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 hypertension | 0 Participants with DLT |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 febrile neutropenia | 0 Participants with DLT |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 hypertension | 1 Participants with DLT |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Participants with DLTs | 1 Participants with DLT |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 thrombocytopenia | 0 Participants with DLT |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 thrombocytopenia | 1 Participants with DLT |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Participants with DLTs | 2 Participants with DLT |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 hypertension | 1 Participants with DLT |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Dose Limiting Toxicity (DLT) of Lenvatinib Administered in Combination With Dacarbazine (for Phase 1b) | Grade 3 febrile neutropenia | 1 Participants with DLT |
Primary
Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs)
Safety assessments consisted of monitoring and recording all AEs, including all Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) grades, and SAEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. Details of AEs and SAEs are provided in the reported adverse event section.
Time frame: From signing of informed consent up to 30 days after the last dose, up to approximately 2 years
Population: Safety Analysis Set: All participants enrolled in the Phase 1b and Phase 2 portion of this study, except for those who (i) dropped out of the study prior to receiving any study drug, or (ii) were without any safety assessment following the first dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | AEs | 3 Participants |
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | SAEs | 2 Participants |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | AEs | 7 Participants |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | SAEs | 4 Participants |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | AEs | 6 Participants |
| 22 mg Lenvatinib + Dacarbazine (Phase 1b) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | SAEs | 2 Participants |
| 20 mg Lenvatinib + Dacarbazine (Phase 2) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | SAEs | 16 Participants |
| 20 mg Lenvatinib + Dacarbazine (Phase 2) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | AEs | 40 Participants |
| Dacarbazine (Phase 2) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | AEs | 31 Participants |
| Dacarbazine (Phase 2) | Number of Participants With Adverse Events/Serious Adverse Events (AEs/SAEs) | SAEs | 1 Participants |
Secondary
Progression Free Survival (PFS) (for Phase 2)
PFS was defined as the time from the date of randomization of a participant until (1) the date of first documented progression of such participant's disease based on Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST v. 1.1) or (2) the date of such participant's death due to any cause. Progression was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions, based on Investigator assessment according to RECIST 1.1. If missing assessments, imputed dates were used in the analysis.
Time frame: From the date of randomization until the date of disease progression or death (whichever was earlier) or up to approximately 2 years
Population: All randomized participants who received at least one dose of study drug without major protocol eligibility violations were included in the Modified Intent-to-Treat (MITT) Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 16 mg Lenvatinib + Dacarbazine (Phase 1b) | Progression Free Survival (PFS) (for Phase 2) | 19.1 Weeks |
| 20 mg Lenvatinib + Dacarbazine (Phase 1b) | Progression Free Survival (PFS) (for Phase 2) | 7.0 Weeks |
Comparison: The current study was not powered or designed to determine superiority of the '20 mg Lenvatinib + Dacarbazine (Phase 2)' arm compared with 'Dacarbazine (Phase 2) ' arm.95% CI: [0.23, 0.75]
Other Pre-specified
Overall Response Rate (ORR) (for Phase 2)
ORR, defined as percentage of participants with best confirmed response (complete response \[CR\] or partial response \[PR\]). A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded.
Time frame: From the date of randomization until disease progression or death or up to approximately 2 years
Other Pre-specified
Overall Survival (OS) (for Phase 2)
OS, defined as the time from the date of randomization until the date of death. Few events of deaths (9 events in the Lenvatinib + Dacarbazine arm and 4 events in the Dacarbazine arm) were reported to calculate the median OS or to draw conclusions regarding the OS.
Time frame: From the date of randomization until death or up to approximately 2 years
Other Pre-specified
Time to Progression (TTP) (for Phase 2)
TTP, defined as the time from the date of randomization until the date of progressive disease.
Time frame: From the date of randomization until disease progression or death or up to approximately 2 years