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

This study has been terminated.
(PI left Moffitt)
Sponsor:
Collaborator:
BioNumerik Pharmaceuticals, Inc.
Information provided by:
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT00358319
First received: July 27, 2006
Last updated: November 21, 2013
Last verified: February 2011
  Purpose

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.


Condition Intervention Phase
Malignant Melanoma
Drug: Karenitecin
Drug: Valproic Acid
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Valproic Acid and Karenitecin for Metastatic Malignant Melanoma

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Safety profile of Valproic Acid (VPA) and Karenitecin [ Time Frame: Average of 6 months ] [ Designated as safety issue: Yes ]
  • Maximum tolerated dose (MTD) of Valproic Acid and Karenitecin [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]
  • Response rate [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]
  • Time to progression (TTP) [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]
  • Overall survival (OS) [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetic parameters of VPA and Karenitecin [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]
  • Relationship between topo I expression, location and DNA strand breakage [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]
  • Patient response to this drug combination [ Time Frame: Average of 6 months ] [ Designated as safety issue: No ]

Enrollment: 42
Study Start Date: March 2005
Study Completion Date: April 2007
Primary Completion Date: April 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I
Dose escalation phase
Drug: Karenitecin Drug: Valproic Acid
Other Name: VPA
Experimental: Phase II
All patients enrolled in the Phase II will be treated with Valproic Acid (VPA) and Karenitecin using the dosing schedule determined to be the Maximum Tolerated Dose (MTD) in Phase I.
Drug: Karenitecin Drug: Valproic Acid
Other Name: VPA

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00358319

Locations
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
BioNumerik Pharmaceuticals, Inc.
Investigators
Principal Investigator: Adil Daud, M.D. UCSF (formerly at H. Lee Moffitt Cancer Center & Research Institute)
  More Information

Additional Information:
No publications provided

Responsible Party: Adil Daud, M.D., UCSF (formerly with H. Lee Moffitt Cancer Center and Research Institute)
ClinicalTrials.gov Identifier: NCT00358319     History of Changes
Other Study ID Numbers: MCC-13991
Study First Received: July 27, 2006
Last Updated: November 21, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Valproic Acid (VPA)
Karenitecin
Malignant Melanoma
Histone deacetylases (HDAC)inhibitors
Topoisomerase I inhibitor
metastatic

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
Valproic Acid
Camptothecin
Histone Deacetylase Inhibitors
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on September 22, 2014