Metastatic Melanoma
Conditions
Keywords
stage IV melanoma, recurrent melanoma
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.
Interventions
DIETARY_SUPPLEMENTCalcitriol
The patient will receive calcitriol in capsule form by mouth on Days 1 and 15 of every cycle
DRUGTemozolomide
The patient will receive temozolomide in capsule form by mouth on Days 2-8 and 16-22 of each 28 study treatment cycle
Sponsors
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide | From start of treatment, up to 12 cycles where 1 cycle equals 28 days | 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. |
| Number of Patients With Toxicity | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response | At baseline and every 8 weeks during treatment for a maximum of 12 cycles where one cycle equals 28 days. | 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. |
| The Relationship Between Vitamin D-receptor Gene Polymorphisms and Tumor Response | Baseline and at disease progression or when patient goes off study up to a maximum of 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on January 13, 2005 with an accrual goal of between 19-28 patients. Accrual was suspended on March 22 2007, reopening May 7 2007, suspended again January 4, 2008, reopening February 14 2008 both times for toxicity evaluations. The study closed permanently on October 28, 2011 with 20 patients enrolled on the study.
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide and Calcitriol (Cohort 1-3+Expansion) 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 | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Completed 12 Cycles of Treatment | Adverse Event | 0 | 0 | 0 | 1 |
| Completed 12 Cycles of Treatment | Progressive Disease | 0 | 1 | 0 | 1 |
| Completed 4 Cycles of Treatment | Progressive disease | 1 | 1 | 2 | 5 |
| Completed DLT Period/1st Cycle | Progressive Disease | 1 | 0 | 0 | 1 |
| Follow up Until Death | Alive at last data cut point | 1 | 0 | 0 | 1 |
| Reached 1st Response/2 Cycles | Progressive Disease | 2 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Temozolomide and Calcitriol (Cohort 1-3+Expansion) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 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 | 20 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 3 | 3 / 3 | 9 / 10 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 3 / 3 | 10 / 10 |
| serious Total, serious adverse events | 2 / 4 | 1 / 3 | 2 / 3 | 4 / 10 |
Outcome results
Primary
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.
Time frame: From start of treatment, up to 12 cycles where 1 cycle equals 28 days
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide | 0 DLT |
| Cohort 2 - Temozolomide and Calcitriol | Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide | 0 DLT |
| Cohort 3 - Temozolomide and Calcitriol | Number and Frequency of Dose Limiting Toxicities (DLTs) With High-dose Calcitriol in Combination With Temozolomide | 0 DLT |
Primary
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.
Time frame: 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
Population: All patients that receive one dose of study drug were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Thrombocytopenia | 1 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vomiting | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Lymphopenia | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vascular | 1 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anemia | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Leukopenia | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Nausea | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anorexia | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Rash | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Fatigue | 0 participants |
| Cohort 1 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Hemorrhage | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Fatigue | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Hemorrhage | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anemia | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Lymphopenia | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Nausea | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anorexia | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vomiting | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Rash | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Leukopenia | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vascular | 0 participants |
| Cohort 2 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Thrombocytopenia | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Rash | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Thrombocytopenia | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vascular | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Nausea | 1 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vomiting | 1 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Leukopenia | 1 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Fatigue | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anemia | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Lymphopenia | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Hemorrhage | 0 participants |
| Cohort 3 - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anorexia | 0 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Fatigue | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anorexia | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Hemorrhage | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Leukopenia | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vomiting | 0 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Nausea | 0 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Rash | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Vascular | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Thrombocytopenia | 1 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Lymphopenia | 2 participants |
| Expansion - Temozolomide and Calcitriol | Number of Patients With Toxicity | Anemia | 2 participants |
Secondary
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.
Time frame: Baseline and at disease progression or when patient goes off study up to a maximum of 12 months
Population: 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.
Secondary
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.
Time frame: At baseline and every 8 weeks during treatment for a maximum of 12 cycles where one cycle equals 28 days.
Population: 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)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Tumor Response | Complete Response | 0 Participants |
| Cohort 1 - Temozolomide and Calcitriol | Tumor Response | Partial Response | 2 Participants |
| Cohort 1 - Temozolomide and Calcitriol | Tumor Response | Stable Disease | 1 Participants |
| Cohort 1 - Temozolomide and Calcitriol | Tumor Response | Progressive Disease | 17 Participants |
Post Hoc
Overall Response Rate
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.
Time frame: From the start of treatment, every 2 cycles where 1 cycle equals 28 days, for a maximum of 12 cycles
Population: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Overall Response Rate | 2 Participants |
Post Hoc
Overall Survival
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.
Time frame: From the first day of treatment until death from any cause, up to a maximum of 6 and half years
Population: 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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Overall Survival | 5.5 Months |
Post Hoc
Overall Survival (OS) Stratified by Vitamin D-Receptor (VDR) Gene Polymorphisms
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.
Time frame: at baseline and until death from any cause up to 6 and half years
Population: 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)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Overall Survival (OS) Stratified by Vitamin D-Receptor (VDR) Gene Polymorphisms | VDR genotype (tt+/-ff) | 3.8 Months |
| Cohort 1 - Temozolomide and Calcitriol | Overall Survival (OS) Stratified by Vitamin D-Receptor (VDR) Gene Polymorphisms | non tt+/-ff VDR genotype | 7.4 Months |
Post Hoc
Time to Progression
Time to progression (TTP) is measured from the start of treatment until the time of first documentation of disease progression.
Time frame: From the start of treatment, until progressive disease, up to 12 months
Population: 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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Temozolomide and Calcitriol | Time to Progression | 1.81 Months |