Melanoma, Uveal
Conditions
Keywords
Melanoma, Uveal, Pembrolizumab, Phase 2, Lenvatinib
Brief summary
The purpose of this study is to evaluate the efficacy of lenvatinib and pembrolizumab to treat metastatic uveal melanoma.
Detailed description
This is a phase II, single arm, single institution clinical trial. Adults (age≥18 years-old) with immune checkpoint inhibitor naïve metastatic uveal melanoma will be evaluated for eligibility. Eligible participants will be treated with the combination of Lenvatinib 20 mg daily + pembrolizumab 200 mg IV every 3 weeks for a maximum of 2 years.
Interventions
DRUGPembrolizumab
200 mg IV every 3 weeks for a maximum of 2 years.
DRUGLenvatinib
20 mg daily for a maximum of 2 years.
Sponsors
Providence Health & Services
Merck Sharp & Dohme LLC
Eisai Inc.
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
* Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic uveal melanoma will be enrolled in this study. * Male participants must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of Lenvatinib and refrain from donating sperm during this period. * Female participants are eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR 2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days post pembrolizumab or post Lenvatinib whichever occurs last. * The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. * Have measurable disease based on iRECIST. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. * Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. If slides are only available, ten slides would be required. Newly obtained biopsies are preferred to archived tissue. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. * Have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 7 days prior to the start of study intervention. * Subjects must agree to undergo paired fresh tumor biopsy specimens (to be collected pre-treatment and day #15). Subjects with tumor metastases that are not amenable to image guided biopsies or who have a contraindication to biopsy (including but not limited to anticoagulation therapy that cannot be interrupted for a biopsy) are still eligible for participation in the clinical trial without undergoing biopsies.
Exclusion criteria
* A WOCBP who has a positive serum pregnancy test within 24 hours prior to the first dose of study intervention (see Appendix 3). * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Prior therapy with Tebentafusp is permitted. Prior liver directed therapy is permitted (including but not limited to radioembolization, chemoembolization, immunoembolization, radio-frequency ablation, external beam radiation and resection). * Participants previously treated with radiation therapy must have recovered from all radiation-related toxicities and not require corticosteroids. * Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed-virus vaccines and mRNA vaccines are allowed. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early stage bladder cancer, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. * Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention. * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. * Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. * Has an active infection requiring systemic therapy. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. * Has had an allogenic tissue/solid organ transplant. * Uncontrolled blood pressure (Systolic BP\>140 mmHg or diastolic BP \>90 mmHg) in spite of an optimized regimen of antihypertensive medication. * Electrolyte abnormalities that have not been corrected * Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening. * Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. * Subjects having ≥2+ proteinuria on urine dipstick testing. However, subjects with ≥2+ proteinuria on urine dipstick testing may undergo a 24-hour urine collection for quantitative assessment of proteinuria. Subjects with \<1 g/24-hour proteinuria are eligible for participation. * Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. * Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin \[ß-hCG\] (or human chorionic gonadotropin \[hCG\]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG \[or hCG\]). * Females of child-bearing potential must be willing to use effective contraception during study and for 120 days after the last dose * The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Effect of Lenvatinib Plus Pembrolizumab on Progression Free Survival | An average of 6 months and 7 days from the time of enrollment. | Progression free survival, defined as the time from enrollment to the first documented evidence of disease progression or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | 6 weeks after treatment discontinuation | Objective response rate (complete and partial responses assessed by iRECIST) |
| Evaluate the Effect of Treatment With Lenvatinib Plus Pembrolizumab on Overall Survival | 12 weeks post treatment discontinuation | Overall survival, defined as the time from enrollment to death (resulting from any cause). |
| Evaluate the Safety and Tolerability of Treatment With Lenvatinib Plus Pembrolizumab in Patients With Metastatic Uveal Melanoma | 30 days after last treatment dose, on average 5 months from the start of treatment. | Number of participants who experienced dose reduction or treatment discontinuation due to treatment related adverse events (TRAE). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMatthew Taylor, MD
Providence Health & Services
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Lenvatinib Lenvatinib 20 mg daily plus pembrolizumab 200 mg IV every 3 weeks.
Pembrolizumab: 200 mg IV every 3 weeks for a maximum of 2 years.
Lenvatinib: 20 mg daily for a maximum of 2 years. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Pembrolizumab + Lenvatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| ECOG Performance Status ECOG PS 0 (Asymptomatic) | 6 Participants |
| ECOG Performance Status ECOG PS 1 (Symptomatic but completely ambulatory) | 0 Participants |
| ECOG Performance Status ECOG PS 2 (Symptomatic, <50% in bed during the day) | 0 Participants |
| ECOG Performance Status ECOG PS 3 (Symptomatic, >50% in bed, but not bedbound) | 0 Participants |
| ECOG Performance Status ECOG PS 4 (Bedbound) | 0 Participants |
| ECOG Performance Status ECOG PS 5 (Death) | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 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 | 0 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 |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 |
Outcome results
Primary
Evaluate the Effect of Lenvatinib Plus Pembrolizumab on Progression Free Survival
Progression free survival, defined as the time from enrollment to the first documented evidence of disease progression or death.
Time frame: An average of 6 months and 7 days from the time of enrollment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Evaluate the Effect of Lenvatinib Plus Pembrolizumab on Progression Free Survival | 165 days |
Secondary
Evaluate the Effect of Treatment With Lenvatinib Plus Pembrolizumab on Overall Survival
Overall survival, defined as the time from enrollment to death (resulting from any cause).
Time frame: 12 weeks post treatment discontinuation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Evaluate the Effect of Treatment With Lenvatinib Plus Pembrolizumab on Overall Survival | 287 Days |
Secondary
Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab
Objective response rate (complete and partial responses assessed by iRECIST)
Time frame: 6 weeks after treatment discontinuation
Population: Tumor assessments were not completed for 2 patients after treatment discontinuation due to disease progression.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab + Lenvatinib | Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | iCR (Complete Response) | 0 Participants |
| Pembrolizumab + Lenvatinib | Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | iPR (Partial Response) | 0 Participants |
| Pembrolizumab + Lenvatinib | Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | iSD (Stable Disease) | 3 Participants |
| Pembrolizumab + Lenvatinib | Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | iUPD (Unconfirmed Progression) | 1 Participants |
| Pembrolizumab + Lenvatinib | Evaluate the Objective Response Rate Resulting From Treatment With Lenvatinib Plus Pembrolizumab | iCPD (Confirmed Progression) | 0 Participants |
Secondary
Evaluate the Safety and Tolerability of Treatment With Lenvatinib Plus Pembrolizumab in Patients With Metastatic Uveal Melanoma
Number of participants who experienced dose reduction or treatment discontinuation due to treatment related adverse events (TRAE).
Time frame: 30 days after last treatment dose, on average 5 months from the start of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Evaluate the Safety and Tolerability of Treatment With Lenvatinib Plus Pembrolizumab in Patients With Metastatic Uveal Melanoma | 0 Participants |