Phase I/II Trial of Valproic Acid and Karenitecin for Melanoma

Malignant Melanoma Clinical Trial

Official title:

Phase I/II Trial of Valproic Acid and Karenitecin for Metastatic Malignant Melanoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00358319
• Other study ID #: MCC-13991
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: July 27, 2006
• Last updated: November 21, 2013
• Start date: March 2005
• Est. completion date: April 2007

Study information

• Verified date: February 2011
• Source: H. Lee Moffitt Cancer Center and Research Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a Phase I study looking at the combination of Valproic Acid (VPA) and Karenitecin to treat patients with metastatic malignant melanoma. We will find the dose-limiting toxicity (DLT) and the highest dose (maximum tolerated dose) of this combination treatment that has acceptable side effects and recommend a Phase II dose level.

There will be seven escalating doses of Valproic acid and one dose escalation step of Karenitecin. Each patient shall receive one cycle of Karenitecin alone (cycle 1 days 1 - 5) followed by the same dose of Karenitecin given in combination with VPA (cycle 2 days 1-7). Patients will receive oral VPA in divided doses for 5 days and Karenitecin starting on the 3rd day every 3 weeks (a treatment cycle).

Treatment will continue until progression of disease or an unacceptable level of toxicity. After 2 cycles of treatment there will be the first efficacy evaluation or restaging of the disease. In the absence of disease progression and if there is continued safety and tolerability, treatment may continue.

Description:

Treatment cycles are every 3 weeks and there are 17 study visits in all.

During Phase I subjects will receive one cycle of Karenitecin alone (cycle 1 days 1-5) and then combination therapy with VPA + Karenitecin (cycle 2 days 1-7)followed by oral VPA in divided doses for 5 days and Karenitecin starting the third day (days 3-7) every 3 weeks. After 2 cycles of treatment there will be the first efficacy evaluation or restaging of the disease.

Dose escalations will continue until unacceptable dose limiting toxicity (DLT) occurs, then dose escalation will be stopped and the previous dose level will be explored. In each dose level, participants will undergo pharmacokinetic (PK) sampling to determine blood levels. The melanoma skin lesions will also be biopsied to measure the effect of the combination therapy.

All patients enrolled in the Phase II will be treated with VPA and Karenitecin using the dosing schedule determined to be the MTD in Phase I. In the absence of disease progression and if there is continued safety and tolerability, treatment may continue in consecutive 3 week cycles.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 42
• Est. completion date: April 2007
• Est. primary completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Same for Phase I & II

• Cytologically/histologically-documented metastatic (stage IV) malignant melanoma

• Age greater than or equal to 18 years old

• ECOG performance status 0-2

• Subjects must be able to give informed consent and be able to follow the guidelines given in the study

• The subject has no major impairment of hematological function, as defined by the following laboratory parameters: WBC > 3.0x109/L; ANC > 1.5 x 109/L; Hgb > 9.0g/dL; PLT >100x109/L. Red blood cell transfusions and repeat evaluations for study entry are allowed

• All subjects of reproductive potential must use an effective method of contraception during the study and three months following termination of treatment (Not applicable to patients with bilateral oophorectomy and/or hysterectomy or to those patients who are postmenopausal.)

• Subjects with biopsiable disease are preferred but not mandatory; subjects with biopsiable disease will be encouraged to undergo biopsy.

Exclusion Criteria:

Phase I:

• Subjects must not have evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) at time of study entry.

• Subjects must have adequate renal and normal hepatic function (creatinine < 1.5 x upper limit of normal (ULN), bilirubin and SGOT (AST) < 1.5 X ULN) obtained within 4 weeks prior to registration.

• Pregnant women are excluded from the study because VPA is known to cause birth defects. Nursing mothers are excluded from this trial as effects on newborns and excretion of either drug in milk is unknown.

• Women of childbearing age must have a negative pregnancy test and be willing to use a highly effective method of contraception. Men who are sexually active must also be willing to use an accepted and effective method of contraception.

• Subjects with uncontrolled CNS metastasis or a history of seizures are excluded. Subjects with stable CNS metastasis (either surgically resected, treated with the gamma knife or stable for 3 months following whole brain radiotherapy are eligible)

Phase II:

• Subjects must not have evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) at time of study entry.

• Subjects must have adequate renal and normal hepatic function (creatinine < 1.5 x upper limit of normal (ULN), bilirubin and SGOT (AST) < 1.5 X ULN) obtained within 4 weeks prior to registration.

• Pregnant women are excluded from the study because VPA is known to cause birth defects. Nursing mothers are excluded from this trial as effects on newborns and excretion of either drug in milk is unknown.

• Women of childbearing age must have a negative pregnancy test and be willing to use a highly effective method of contraception. Men who are sexually active must also be willing to use an accepted and effective method of contraception.

• Subjects with uncontrolled CNS metastasis or a history of seizures are excluded. Subjects with stable CNS metastasis (either surgically resected, treated with the gamma knife or stable for 3 months following whole brain radiotherapy are eligible)

• Subjects who have been previously treated with more than 2 prior chemotherapy regimens. Any previous immunotherapy regimens are allowed.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malignant Melanoma
• Melanoma

Intervention

Drug:
• Karenitecin

• Valproic Acid

Locations

Country	Name	City	State
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
H. Lee Moffitt Cancer Center and Research Institute	BioNumerik Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety profile of Valproic Acid (VPA) and Karenitecin		Average of 6 months	Yes
Primary	Maximum tolerated dose (MTD) of Valproic Acid and Karenitecin		Average of 6 months	No
Primary	Response rate		Average of 6 months	No
Primary	Time to progression (TTP)		Average of 6 months	No
Primary	Overall survival (OS)		Average of 6 months	No
Secondary	Pharmacokinetic parameters of VPA and Karenitecin		Average of 6 months	No
Secondary	Relationship between topo I expression, location and DNA strand breakage		Average of 6 months	No
Secondary	Patient response to this drug combination		Average of 6 months	No

External Links

•   Moffiitt Cancer Center Clinical Trials Website