Phase I/II Study of High-Dose Calcitriol Plus Temodar for Patients With Metastatic Melanoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Calcitriol may help temozolomide kill more tumor cells by making them more sensitive to the drug. Calcitriol may also stop the growth of melanoma by blocking blood flow to the tumor. PURPOSE: This phase I/II trial is studying the best dose of calcitriol, the side effects of calcitriol when given together with temozolomide, and to see how well they work in treating patients with metastatic stage IV melanoma.

Detailed Description
-----------------
* Phase I: Patients receive oral calcitriol on days 1 and 15 and oral temozolomide on days 2-8 and 16-22. Treatment repeats every 28 days for 2 courses in the absence of unacceptable toxicity. Responding patients continue therapy for up to 6 courses in the absence of unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of calcitriol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose limiting toxicity. Phase II: Patients receive temozolomide and calcitriol at the MTD as in phase I. After completion of study treatment, patients are followed every 3 months.

Official Title
-----------------
A Phase I/II Study of High-Dose Calcitriol in Combination With Temozolomide for Patients With Metastatic Melanoma

Conditions
-----------------
Metastatic Melanoma

Intervention / Treatment
-----------------
* Dietary Supplement: Calcitriol
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed malignant melanoma Any primary tumor site Stage IV disease CNS metastases allowed Measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension as ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan Must have had at least 1 prior systemic therapy Negative pregnancy test Fertile patients must use effective contraception Patients with no prior systemic therapy are eligible provided they are not candidates for high-dose interleukin-2 Recovered from all toxic effects of prior therapy More than 4 weeks since prior and no concurrent radiotherapy, chemotherapy, or immunotherapy More than 4 weeks since prior and no concurrent radiotherapy, chemotherapy, or immunotherapy Fertile patients must use effective contraception Exclusion Criteria: Life expectancy less than 4 months known HIV positivity evidence of active infection requiring antibiotic therapy other malignancy within the past 5 years except surgically resected basal cell or squamous cell skin cancer significant medical disease which, in the opinion of the investigator, may interfere with study completion pregnant or nursing Negative pregnancy test prior temozolomide or dacarbazine investigational agent within 4 weeks prior to study entry concurrent magnesium-containing antacids, digitalis, bile-resin binding drugs, or calcium supplements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 dose escalation design study. (3) patients per dose stratum will be entered in the following cohorts: Cohort 1 - Temozolomide and Calcitriol 0.2mcg/kg days 1 + 15 Cohort 2 - Temozolomide and Calcitriol 0.3 mcg/kg days 1 + 15 Cohort 3 - Temozolomide and Calcitriol 0.5 mcg/kg days 1 + 15 Temozolomide dose of 150 mg/m2 will be administered orally on days 2-8 and 16-22 every 28 day cycle in each cohort. If 1 patient experiences dose limiting toxicity (DLT) at any dose, that cohort will be expanded to 6 patients. If 2 patients experience DLT in that cohort, further dose escalation will cease and the cohort immediately preceding that cohort will be considered the maximum tolerated dose (MTD). Alternatively, if no more patients experience DLT, then dose will be escalated to the next cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Temozolomide and Calcitriol<br>Temozolomide dose of 150 mg/m2 will be administered orally on days 2-8 and 16-22 every cycle where 1 cycle equals 28 days. Calcitriol dose of 0.2 mcg/kg will be administered orally on days 1 and 15 every cycle where 1 cycle equals 28 days. | Dietary Supplement: Calcitriol<br>* The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle<br>Drug: Temozolomide<br>* The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle<br>|
| Experimental: Cohort 2 - Temozolomide and Calcitriol<br>Temozolomide dose of 150 mg/m2 will be administered orally on days 2-8 and 16-22 every cycle where 1 cycle equals 28 days. Calcitriol dose of 0.3 mcg/kg will be administered orally on days 1 and 15 every cycle where 1 cycle equals 28 days. | Dietary Supplement: Calcitriol<br>* The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle<br>Drug: Temozolomide<br>* The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle<br>|
| Experimental: Cohort 3 - Temozolomide and Calcitriol<br>Temozolomide dose of 150 mg/m2 will be administered orally on days 2-8 and 16-22 every cycle where 1 cycle equals 28 days. Calcitriol dose of 0.5 mcg/kg will be administered orally on days 1 and 15 every cycle where 1 cycle equals 28 days. | Dietary Supplement: Calcitriol<br>* The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle<br>Drug: Temozolomide<br>* The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle<br>|
| Experimental: Expansion - Temozolomide and Calcitriol<br>Temozolomide dose of 150 mg/m2 will be administered orally on days 2-8 and 16-22 every cycle where 1 cycle equals 28 days. Calcitriol dose of 0.5 mcg/kg will be administered orally on days 1 and 15 every cycle where 1 cycle equals 28 days. | Dietary Supplement: Calcitriol<br>* The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle<br>Drug: Temozolomide<br>* The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide | Determine number and frequency of dose limiting toxicities (DLT) of high-dose calcitriol when administered with temozolomide in patients with metastatic melanoma for up to 12 cycles of therapy, where 1 cycle equals 28 days. 3 patients per dose cohort will be entered into the trial at doses of 0.2, 0.3, and 0.5 mcg/kg of calcitriol administered orally. If 1 patient experiences dose limiting toxicity (DLT) at any dose, that dose cohort will be expanded to a maximum of 6 patients. If 1 additional patient experiences DLT at that dose stratum, further dose escalation will cease and the dose cohort immediately preceding the dose cohort where the 2 experiences of DLT occurred will be considered the MTD. If no additional patients experience DLT, dose escalation to the next higher dose stratum will take place. DLT is defined as National Cancer Institute Common Toxicity Criteria, version 3.0 grade 3 toxicity determined to be related to calcitriol. | From start of treatment, up to 12 cycles where 1 cycle equals 28 days | 
| Number of Patients With Toxicity | Toxicity will be assessed for each patient on a seven-day on/seven-day off temozolomide in combination with high-dose calcitriol for every 2 weeks for up to 12 cycles where 1 cycle equals 28 days. Toxicity will be assessed during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0) and defined by any toxicity determined to be at least possibly related to either study drug (temozolomide or calcitriol). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Grade 3 and grade 4 toxicities where relatedness to either study drug could not be ruled out were collected and recorded only. | From the start of treatment and every 2 weeks for a maximum of 12 cycles, and 30 days post last treatment, where 1 cycle equals 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Determine best tumor response during treatment. Response and progression was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | At baseline and every 8 weeks during treatment for a maximum of 12 cycles where one cycle equals 28 days. | 
| The Relationship Between Vitamin D-receptor Gene Polymorphisms and Tumor Response | Investigate the relationship between vitamin D-receptor (VDR) gene polymorphisms in Taq1 and Fok1 (analyzed from baseline blood sample) and tumor response. VDR gene analysis was completed using PCR-RFLP based assays. | Baseline and at disease progression or when patient goes off study up to a maximum of 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV melanoma, recurrent melanoma