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

• ClinicalTrials.gov Identifier: NCT01328535
• Recruitment Status: Completed
• First Posted: April 4, 2011
• Results First Posted: November 7, 2018
• Last Update Posted: October 22, 2020
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

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 (Clinical Trial)
• 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: January 2011
• Actual Primary Completion Date: June 22, 2013
• Actual Study Completion Date: July 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 Name: Staining; Procedure: biopsy; Optional correlative studies; Other Name: biopsies; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Progression-Free Survival at 4 Months [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

United States, Minnesota

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

More Information

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01328535
• Other Study ID Numbers: MC1076; NCI-2011-00449 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); MC1076 ( Other Identifier: Mayo Clinic Cancer Center ID ); 10-008497 ( Other Identifier: Mayo Clinic IRB )
• First Posted: April 4, 2011
• Results First Posted: November 7, 2018
• Last Update Posted: October 22, 2020
• Last Verified: February 2019

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents