E2607: A Phase II Trial of Dasatinib in KIT-Positive Patients with Unresectable Locally Advanced or Stage IV Mucosal, Acral and Vulvovaginal Melanomas
Study Design (Based on data as of august 5, 2010)
1. Screen patients for KiT mutation status (either locally or centrally) and enroll KiT+ cases only,
2. KiT+ mutation rate is low in sun-damaged cases x therefore this subgroup will be eliminated
3. The Gynecologic oncology Group will join the study to enhance the accrual of vulvovaginal melanoma cases
4. The statistical design has been revised with the assumption that the KiT mutation rate is 6-7%.
Patients will receive dasatinib 70 mg orally twice daily (two tablets; one 50 mg tablet and one 20 mg tablet) on an open-label, single-arm basis. The medication is to be taken once in the morning and once in the evening with or without food. The cycle length of dasatinib is 21 days; however, the medication should be taken every day. There are no breaks between cycles. These are flat doses of the drugs. There is no adjustment of dose for BSa. Patients who are tolerating treatment may continue on therapy until disease progression.
it is assumed that approximately 15 (50%) of the patients to be accrued will have their melanoma's c-KiT mutation status determined locally. For the remaining patients, it is estimated that approximately 250 patients with acral or mucosal (including vulvovaginal) melanoma subtypes will be screened centrally for KiT mutations. of these, it is expected that 15 KiT mutation+ subjects will be enrolled in this study. of the accrued patients, we expect that there will be 12 KiT+ cases with vulvovaginal melanoma and 18 other melanoma cases. including the pre-screening of 250 cases, enrolling 30 KiT + cases is expected to be completed in 3 years.
if dasatinib can improve the response rate from 15% to 37% in KiT+ cases, we will conclude this is a promising regimen for KiT+ cases. note that the main sample size calculation presented in this section is based on the combined eCoG and GoG populations. However, at the end of the study, separate analyses in eCoG and GoG populations will also be performed.
a maximum of 30 (for 28 eligible) patients will be registered with a two-stage accrual design. if dasatinib shows evidence of at least 37% response rate, we would consider this a promising drug for a further study. However to conserve patient resources, we wish to minimize accrual if the response rate is less than 15%.
in the first stage, 15 cases (assuming 14 eligible) will be accrued. if there are at least 3 responses, accrual will continue to 30 (assuming 28 eligible). if there are at least 7 responses this will be considered successful. This design will provide 90% power with a one-sided type i error rate of .10. if the response rate is low (15%), there is 65% chance of stopping the study early.
Given the small percentage of KiT+ rate, the screening process will continue while interim analysis is being conducted.
The duration of response for responders, progression-free survival and safety profile of dasatinib will be evaluated. Descriptive statistics will be provided for this data.
Pre-Registration (Step 0)
1. Age >= 18 years.
2. ECOG performance status of 0 or 1.
3. Histological or cytological confirmed melanoma that is metastatic or unresectable.
Patients must have measurable disease (at least one measurable lesion) as defined by RECIST criteria. NOTE: All sites of disease must be evaluated within 4 weeks prior to registration to treatment (Step 1).
Patients must have a history of melanoma of one of the following subtypes:
a. Acral (as defined as occurring on the palms, soles, or subungual sites),
b. Melanoma arising from the vagina and/or vulva
c. Melanoma arising on other mucosal surface (not vagina or vulva)
4. c-KIT mutation status determination, local versus central assessments. At least one must apply:
a. Performed locally by Polymerase Chain Reaction (PCR) and sequencing prior to pre-registration: The melanoma harbors at least one mutation in exon 9, 11, 13, 17 or 18 of the c-KIT gene.
Registration to Step 1 may occur upon confirmation of pre-registration
b. Performed locally by Polymerase Chain Reaction (PCR) and sequencing prior to pre-registration: If the melanoma harbors at least one mutation in the c-KIT gene but is not in an exon listed in protocol section 18.104.22.168 or is uncertain whether it is in one of these exons then eligibility to register to step 1 requires approval of a designated central reviewer. Submit the cKIT report within 24 hours after pre-registration as indicated in protocol Appendix VI.
c. If local assessment is not possible, metastatic (preferred) or primary tumor tissue should be on hand PRIOR to pre-registration and will be submitted to Massachusetts General Hospital x Pathology (MGH) within 5 working days following pre-registration as outlined in protocol section 10.
If submission of tissue will be submitted more than 5 working days after pre-registration, immediately notify MGH (Massachusetts General Hospital) (617-726-0503, firstname.lastname@example.org) to discuss the potential submission timeline.
IMPORTANT: If the c-KIT status will be determined by MGH, strict attention is to be paid to the timeframes dictated in protocol section 3.2. Specifically, clinical assessments which must fall within 4 weeks of registration to treatment (Step 1) may be performed or repeated during pre-registration to fall within the required timeframe.
5. Both naive and previous systemically treated patients are included.
a) Prior chemotherapy or immunotherapy is permitted.
b) Prior investigational agents are permitted, however, no prior treatment with targeted therapies directed to c-KIT/PDGFR allowed (e.g., imatinib or sunitinib).
c.) Limb perfusion allowed.
d.) If radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions.
6. Spanish speaking participants are eligible to participate.
Registration (Step 1)
1. The patient must meet the eligibility criteria outlined as Pre-Registration (Step 0)
2. The melanoma must harbor a c-KIT mutation determined by PCR and sequencing as defined in Step 0 either by:
a. Local Assessment:
1. Mutation in exon 9,11,13,17 or 18
2. cKIT positive mutation status determined by MGH
3. Patients must have measurable disease (at least one measurable lesion) as defined by RECIST criteria. All sites of disease must be evaluated within 4 weeks prior to registration to treatment (Step 1).
4. If patient has received previous systemic treatment, at least 4 weeks must have elapsed since the last chemotherapy, radiotherapy or immunotherapy and the beginning of protocol therapy and the patient must have recovered from toxicity due to the previous therapy (i.e., toxicity has resolved to baseline or is deemed irreversible).
5. Patients with a history or clinical evidence of brain metastasis must have completed radiation therapy or surgical treatment of brain lesions and have no evidence of CNS progression for at least eight weeks at the time of registration. Patients must not require corticosteroids for treatment of cerebral edema from brain metastases. Patients must be evaluated with a head MRI within 4 weeks prior to registration.
6. Women of childbearing potential must not be pregnant or breastfeeding.
All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months
7. Women of childbearing potential and sexually active males must be strongly advised to use an accepted method of contraception
8. Patients must have the following within 4 weeks prior to registration:
CT Chest with IV and oral agent
CT Pelvis/Abdomen with IV and oral agent
MRI Brain with gadolinium
For patients with known bone metastases, elevated alkaline phosphatase or symptoms raising suspicion of bone metastases, a baseline bone scan is required.
9. Baseline laboratory values (evaluated within 4 weeks prior to registration):
a. White Blood Count > 3,000/mm3 WBC
b. Absolute Granulocyte Count > 1,500/mm3 AGC
c. Platelet Count > 100,000/mm3 Platelet
d. Serum creatinine < 2.0 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) > 40 ml/min (drug is not cleared by the kidney)
(CrCl = WT (kg) x (140-age)*/72 x Cr. Level, * female x 0.85)
f. Total Bilirubin < 1.5 x ULN (<3.0 x ULN in the presence of Gilbert[Single Quote]s disease)
g. AST and ALT < 2.5 x ULN (< 5.0 ULN in the presence of liver metastases)
h. Serum potassium and magnesium levels within institutional normal limits. Patients with low potassium and magnesium levels may be repleted to allow for protocol entry.
i. Total serum calcium or ionized calcium level > institutional lower limit of normal.
j. INR < 1.5 and PTT within normal limits (Patients who are on therapeutic anticoagulation with warfarin should have documentation of INR < 1.5 or PTT within normal limits prior to initiating that therapy).