Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Bone Density Conservation Agents

Micronutrients

Vasoconstrictor Agents

Temozolomide

Calcitriol

Antineoplastic Agents, Alkylating

Alkylating Agents

Hormones

Calcium

Calcium, Dietary

Vitamins

Trace Elements

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.

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.

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.

The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle

The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle

Timothy M. Kuzel, MD

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.

\* 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.

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.

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

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

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.

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.

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.

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.

National Cancer Institute (NCI)

Northwestern University

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.

Calcitriol: The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle

Temozolomide: The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle

Cohort 1 - Temozolomide and Calcitriol

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.

Calcitriol: The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle

Temozolomide: The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle

Cohort 2 - Temozolomide and Calcitriol

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.

Calcitriol: The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle

Temozolomide: The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle

Cohort 3 - Temozolomide and Calcitriol

Expansion - Temozolomide and Calcitriol

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, 0.3, or 0.5 mcg/kg will be administered orally on days 1 and 15 every cycle where 1 cycle equals 28 days.

Calcitriol: The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle

Temozolomide: The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle

Temozolomide and Calcitriol (Cohort 1-3+Expansion)

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Clinical Trials Office

1 patient enrolled in cohort 1 was not evaluable for this outcome measure as the patient only received 8 days of treatment. Patients enrolled in the expansion cohort were not evaluable for this outcome measure.

Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide

Thrombocytopenia

Vascular

Nausea

Vomiting

Leukopenia

Fatigue

Anemia

Lymphopenia

Hemorrhage

Rash

Anorexia

All patients that receive one dose of study drug were evaluable for this outcome measure.

Number of Patients With Toxicity

Cohort results for this outcome measure are combined as the objective was to determine the tumor response of patients with this drug combination (dose was irrelevant)

Tumor Response

Cohort results for this outcome measure are combined as the objective was to investigate relationship of VDR gene polymorphisms present and tumor response of patients with this drug combination (dose was irrelevant) Data was not collected or analyzed for this outcome measure.

The Relationship Between Vitamin D-receptor Gene Polymorphisms and Tumor Response

Overall Response Rate (ORR) is defined as percentage of patients who's best response to treatment is complete response plus those with partial response.

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.

Cohort results for this outcome measure are combined as the objective was to determine the ORR of patients with this drug combination (dose was irrelevant)

Overall Response Rate

Time to progression (TTP) is measured from the start of treatment until the time of first documentation of disease progression.

Cohort results for this outcome measure are combined as the objective was to determine the TTP for patients with this drug combination (dose was irrelevant)

Time to Progression

Overall Survival (OS) will be measured from first day of treatment until death of any cause. Patients still alive at the last data cut off point will be censored.

Cohort results for this outcome measure are combined as the objective was to determine the OS of patients with this drug combination (dose was irrelevant)

Overall Survival

VDR genotype (tt+/-ff)

non tt+/-ff VDR genotype

Investigate the relationship between vitamin D-receptor (VDR) gene polymorphisms in Taq1 and Fok1 (analyzed from baseline blood sample) and Overall Survival (OS). VDR gene analysis was completed using PCR-RFLP based assays.

Cohort results for this outcome measure are combined as the objective was to determine the relationship between VDR gene polymorphisms and OS for patients with this drug combination (dose was irrelevant)

Spots Global Cancer Trial Database for Phase I/II Study of High-Dose Calcitriol Plus Temodar for Patients With Metastatic Melanoma

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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