Individualized Temozolomide in Treating Patients With Stage IV Melanoma That Cannot Be Removed By Surgery

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01328535
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 25
• Location: 1
• Arm: 1
• Actual Duration (Months): 90.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IV Melanoma	Drug: temozolomide; Other: flow cytometry; Other: staining method; Procedure: biopsy; Other: laboratory biomarker analysis	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Individualized (Timed) Temozolomide Administration as a Means of Immune Reconstitution in Patients With Metastatic Melanoma
• Actual Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Jun 22, 2013
• Actual Study Completion Date: Jul 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: temozolomide; Given PO; Other Names: SCH 52365 Temodal Temodar TMZ ; Other: flow cytometry; Correlative studies; Other: staining method; Correlative studies; Other Names: Staining ; Procedure: biopsy; Optional correlative studies; Other Names: biopsies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. To Evaluate the Impact of Timed TMZ Chemotherapy on Immune Biomarkers and the Anti-tumor Immune Biorhythms. [6 months]

2. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Roxana Dronca, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01328535
• Other Study ID Numbers: MC1076; NCI-2011-00449; MC1076; 10-008497
• First Posted: Apr 4, 2011
• Last Update Posted: Oct 22, 2020
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Melanoma; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Treatment (Individualized Chemotherapy)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	25
COMPLETED	24
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Individualized Chemotherapy)
Arm/Group Description	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.
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69.5
Sex: Female, Male (Count of Participants)
Female	10 41.7%
Male	14 58.3%
Region of Enrollment (Count of Participants)
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival at 4 Months
Description	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

Outcome Measure Data

Analysis Population Description

Only patients who were evaluable for the primary endpoint were included in the analysis.

Arm/Group Title	Treatment (Timed Individualized Chemotherapy)
Arm/Group Description	Patients with an established biorhythm receive timed 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.
Measure Participants	18
Number (95% Confidence Interval) [percentage of patients]	22.2

2. Secondary Outcome

Title	Progression-Free Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Timed Individualized Chemotherapy)	Treatment (Untimed Individualized Chemotherapy)
Arm/Group Description	Patients with an established biorhythm receive timed 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.	Patients with an established biorhythm receive untimed 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.
Measure Participants	18	6
Median (95% Confidence Interval) [months]	3.4	7.2

3. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Timed Individualized Chemotherapy)	Treatment (Untimed Individualized Chemotherapy)
Arm/Group Description	Patients with an established biorhythm receive timed 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.	Patients with an established biorhythm receive untimed 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.
Measure Participants	18	6
Median (95% Confidence Interval) [months]	23.1	17.5

4. Secondary Outcome

Title	Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Individualized Chemotherapy)
Arm/Group Description	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.
Measure Participants	24
Fatigue	4.2
Febrile Neutropenia	8.3
Neutrophil Count Decreased	8.3
Platelet Count Decreased	25
Sepsis	4.2
Urinary Tract Infection	4.2
White Blood Cell Decreased	8.3
Abdominal Infection	4.2

5. Other Pre-specified Outcome

Title	To Evaluate the Impact of Timed TMZ Chemotherapy on Immune Biomarkers and the Anti-tumor Immune Biorhythms.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	The descriptions & grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation & scientific analysis & is a single MedDRA Lowest Level Term (LLT).
Arm/Group Title	Treatment (Individualized Chemotherapy)
Arm/Group Description	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.
All Cause Mortality
	Treatment (Individualized Chemotherapy)
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	Treatment (Individualized Chemotherapy)
	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)
Blood and lymphatic system disorders
Anemia	1/24 (4.2%)	1
Febrile neutropenia	1/24 (4.2%)	1
Gastrointestinal disorders
Abdominal pain	1/24 (4.2%)	1
Constipation	1/24 (4.2%)	1
General disorders
Fatigue	1/24 (4.2%)	1
Infections and infestations
Abdominal infection	1/24 (4.2%)	1
Sepsis	1/24 (4.2%)	1
Investigations
Neutrophil count decreased	1/24 (4.2%)	1
Platelet count decreased	1/24 (4.2%)	1
White blood cell decreased	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Individualized Chemotherapy)
	Affected / at Risk (%)	# Events
Total	20/24 (83.3%)
Blood and lymphatic system disorders
Anemia	14/24 (58.3%)	55
Blood and lymphatic system disorders - Other, specify	1/24 (4.2%)	1
Febrile neutropenia	1/24 (4.2%)	1
Gastrointestinal disorders
Abdominal pain	1/24 (4.2%)	1
Constipation	3/24 (12.5%)	5
Hemorrhoidal hemorrhage	1/24 (4.2%)	1
Nausea	2/24 (8.3%)	2
Vomiting	1/24 (4.2%)	1
General disorders
Chills	1/24 (4.2%)	1
Fatigue	5/24 (20.8%)	6
Infections and infestations
Soft tissue infection	2/24 (8.3%)	4
Urinary tract infection	1/24 (4.2%)	1
Investigations
Aspartate aminotransferase increased	1/24 (4.2%)	1
Neutrophil count decreased	7/24 (29.2%)	9
Platelet count decreased	17/24 (70.8%)	52
White blood cell decreased	8/24 (33.3%)	10
Metabolism and nutrition disorders
Anorexia	2/24 (8.3%)	2
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb	1/24 (4.2%)	2
Vascular disorders
Hypertension	1/24 (4.2%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.