Recurrent Melanoma, Stage IV Melanoma
Conditions
Brief summary
This clinical trial studies individualized temozolomide (TMZ) in treating patients with stage IV melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as TMZ, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving TMZ at different times, which are determined individually for each patient based on the phase (biorhythm) of the immune system response against the tumor may allow for a better drug response and may kill more tumor cells
Detailed description
PRIMARY OBJECTIVES: I. To assess the clinical activity of timed administration of TMZ therapy in patients with stage IV melanoma who have or have not received prior chemotherapy for metastatic melanoma. SECONDARY OBJECTIVES: I. To assess the toxicity profile of timed administration of TMZ therapy in patients with stage IV melanoma who have or have not received prior chemotherapy for their metastatic disease. II. To evaluate the parameters of immune homeostasis that are associated with the anti-tumor immune biorhythm in order to gain insight into the mechanism of the observed clinical and immunological effect of timed TMZ chemotherapy. III. To evaluate the impact of timed TMZ chemotherapy on immune biomarkers and the anti-tumor immune biorhythms. OUTLINE: Prior to initiation of therapy patients will undergo a period of immunologic monitoring to analyze the bioperiodicity of their anti-tumor immune response. Patients with an established biorhythm will receive TMZ orally (PO) starting on the recommended day for 5 days. Treatment repeats every 21-42 days (based on the established biorhythm) until of disease progression or unacceptable toxicity. Patients without an established biorhythm are given the option to go off study or receive TMZ PO on days 1-5. Courses repeat every 28 days until disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 2 years.
Interventions
DRUGtemozolomide
Given PO
OTHERflow cytometry
Correlative studies
OTHERstaining method
Correlative studies
PROCEDUREbiopsy
Optional correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
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
* Histologic/cytologic proof of stage IV malignant melanoma not amenable to surgery * Any number of previous chemotherapy regimens (except those containing TMZ or dacarbazine \[DTIC\]) in the metastatic setting are allowed as long as \>= 4 weeks have elapsed from last treatment * Measurable disease defined as at least one lesion whose longest diameter can be accurately measured as \>= 1.0 cm with spiral CT scan, or ≥ 2 cm with computed tomography (CT) component of a positron emission tomography (PET)/CT; Note: disease that is measurable by physical examination only is not eligible * Life expectancy of \>= 3 months * Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 * Recovered from side effects that might interfere with the protocol therapy and: - \>= 4 weeks must have elapsed from last radiation treatment to time of study entry - \>= 4 weeks must have elapsed from the last chemotherapy administration to time of study entry * Absolute neutrophil count (ANC) \>= 1500/mL * Platelet count \>= 100,000/mcl * Hemoglobin \>= 9gm/mcl * Creatinine =\< 2.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) =\< 3 x ULN * Negative serum pregnancy test done =\< 7 days prior to registration, for women of childbearing potential only * Ability to understand and the willingness to sign a written informed consent document * Willingness to return to Mayo Clinic Rochester for follow-up, except for some appointments that can be made with the local physician * Patient willing to provide research blood samples
Exclusion criteria
* Receiving any other investigational agents including those for symptom management * Uncontrolled intercurrent illness including, but not limited to, the following: - Active infection - Congestive heart-failure (New York Heart Association \[NYHA\] grade III or IV) * Pregnant or breast feeding women, or women of child-bearing potential (and/or their partners) who are unwilling to utilize an approved method of birth control during the study and for 1 month afterward * History of other malignancy \< 5 years with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only, limited stage prostate cancer treated with surgery or radiation therapy with currently undetectable prostate-specific antigen (PSA), or carcinoma in situ of the cervix * Known standard therapy for the patient's disease that is potentially curative or proven capable of extending life expectancy * Known immunosuppression (i.e. chronic steroid use) or autoimmune disorder * Human immunodeficiency virus (HIV) positive * Current or known history of hepatitis * Previous treatment with DTIC or TMZ * Previous immunotherapy treatment for metastatic disease in the preceding 2 months; Note: immunotherapy in the adjuvant setting is allowed * Previously untreated brain metastases; Note: patients with previously treated brain metastases are allowed as long as these are radiologically stable for \>= 3 months and the patient is off steroids for \>= 4 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival at 4 Months | Time from registration to the earliest date of documentation of disease progression, assessed at 4 months | The distribution of time to progression will be estimated using the method of Kaplan-Meier and the 4 month progression-free rate (percentage) will be provided. Progression is defined as: At least one of the following must be true: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (\< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD. In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Up to 2 years | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined as:At least one of the following must be true: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (\< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD (Section 11.41). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. |
| Overall Survival | Up to 2 years | Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. |
| Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Up to 2 years | The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. |
Other
| Measure | Time frame |
|---|---|
| To Evaluate the Impact of Timed TMZ Chemotherapy on Immune Biomarkers and the Anti-tumor Immune Biorhythms. | 6 months |
| To Evaluate the Parameters of Immune Homeostasis That Are Associated With the Anti-tumor Immune Biorhythm in Order to Gain Insight Into the Mechanism of the Observed Clinical and Immunological Effect of Timed TMZ Chemotherapy | 2 years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Individualized Chemotherapy) Patients with an established biorhythm receive TMZ PO on recommended day for 5 days. Treatment repeats every 21-42 days until disease progression or unacceptable toxicity. Patients without an established biorhythm receive TMZ PO on days 1-5. Courses repeat every 28 days until disease progression or unacceptable toxicity. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 1 |
Baseline characteristics
| Characteristic | Treatment (Individualized Chemotherapy) |
|---|---|
| Age, Continuous | 69.5 years |
| Region of Enrollment United States | 24 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 20 / 24 |
| serious Total, serious adverse events | 3 / 24 |
Outcome results
Primary
Progression-Free Survival at 4 Months
The distribution of time to progression will be estimated using the method of Kaplan-Meier and the 4 month progression-free rate (percentage) will be provided. Progression is defined as: At least one of the following must be true: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (\< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD. In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.
Time frame: Time from registration to the earliest date of documentation of disease progression, assessed at 4 months
Population: Only patients who were evaluable for the primary endpoint were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Timed Individualized Chemotherapy) | Progression-Free Survival at 4 Months | 22.2 percentage of patients |
Secondary
Overall Survival
Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Timed Individualized Chemotherapy) | Overall Survival | 23.1 months |
| Treatment (Untimed Individualized Chemotherapy) | Overall Survival | 17.5 months |
Secondary
Progression-Free Survival
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined as:At least one of the following must be true: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (\< 1.0 cm short axis) and increased to ≥ 1.0 cm short axis during follow-up. At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD (Section 11.41). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Timed Individualized Chemotherapy) | Progression-Free Survival | 3.4 months |
| Treatment (Untimed Individualized Chemotherapy) | Progression-Free Survival | 7.2 months |
Secondary
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either unrelated or unlikely to be related to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Febrile Neutropenia | 8.3 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Fatigue | 4.2 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Neutrophil Count Decreased | 8.3 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Platelet Count Decreased | 25 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Sepsis | 4.2 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Urinary Tract Infection | 4.2 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | White Blood Cell Decreased | 8.3 percentage of patients |
| Treatment (Timed Individualized Chemotherapy) | Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) | Abdominal Infection | 4.2 percentage of patients |
Other Pre-specified
To Evaluate the Impact of Timed TMZ Chemotherapy on Immune Biomarkers and the Anti-tumor Immune Biorhythms.
Time frame: 6 months
Other Pre-specified
To Evaluate the Parameters of Immune Homeostasis That Are Associated With the Anti-tumor Immune Biorhythm in Order to Gain Insight Into the Mechanism of the Observed Clinical and Immunological Effect of Timed TMZ Chemotherapy
Time frame: 2 years