Flavopiridol Plus Radiation Therapy Followed By Gemcitabine Hydrochloride in Treating Patients With Locally Advanced, Unresectable Pancreatic Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00047307
First received: October 3, 2002
Last updated: June 3, 2013
Last verified: June 2013
  Purpose

Drugs used in chemotherapy work different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Flavopiridol may make the tumor cells more sensitive to radiation therapy. Phase I trial to study the effectiveness of combining flavopiridol with radiation therapy followed by gemcitabine hydrochloride in treating patients who have locally advanced, unresectable pancreatic cancer.


Condition Intervention Phase
Adenocarcinoma of the Pancreas
Recurrent Pancreatic Cancer
Stage II Pancreatic Cancer
Stage III Pancreatic Cancer
Stage IV Pancreatic Cancer
Drug: alvocidib
Drug: gemcitabine hydrochloride
Radiation: 3-dimensional conformal radiation therapy
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Alvocidib (Flavopiridol) in Combination With Radiation in Locally Advanced, Non-Operable Pancreatic and Extrahepatic Bile Duct Cancers

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of flavopiridol when administered biweekly in conjunction with radiation for patients with locally advanced pancreatic or extrahepatic bile duct cancer [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Molecular correlates of apoptosis including PARP cleavage and caspase-3 activation, as well as changes in expression of p21, phosphorylation status of pRb and cyclin D1 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Will be summarized by descriptive statistics and used to generate hypothesis for further studies.

  • Molecular correlates of apoptosis including PARP cleavage and caspase-3 activation, as well as changes in expression of p21, phosphorylation status of pRb and cyclin D1 [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    Will be summarized by descriptive statistics and used to generate hypothesis for further studies.


Enrollment: 46
Study Start Date: August 2002
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (alvocidib, gemcitabine hydrochloride, 3DRT)

Patients receive flavopiridol IV over 1 hour twice weekly (on days 1 and 4 or days 2 and 5) for 6 weeks. Concurrently, patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Four weeks after the completion of radiotherapy, patients are re-evaluated*. Beginning within 4-7 weeks after the completion of chemotherapy and radiotherapy, patients receive gemcitabine hydrochloride alone or in combination with another cytotoxic agent or gemcitabine hydrochloride combined with a targeted drug (e.g., erlotinib or bevacizumab) at the discretion of the oncologist. NOTE: *Patients whose imaging studies suggest potential curative resection are referred for a surgical evaluation before initiating gemcitabine hydrochloride therapy. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. Continued (see detailed description)

Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Radiation: 3-dimensional conformal radiation therapy
Undergo 3-dimensional conformal radiation therapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of flavopiridol in combination with radiotherapy followed by gemcitabine in patients with locally advanced, unresectable pancreatic cancer.

II. Determine the toxicity of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of flavopiridol in these patients. II. Determine, preliminarily, the therapeutic activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study of flavopiridol.

Patients receive flavopiridol IV over 1 hour twice weekly (on days 1 and 4 or days 2 and 5) for 6 weeks. Concurrently, patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Four weeks after the completion of radiotherapy, patients are re-evaluated*. Beginning within 4-7 weeks after the completion of chemotherapy and radiotherapy, patients receive gemcitabine hydrochloride alone or in combination with another cytotoxic agent or gemcitabine hydrochloride combined with a targeted drug (e.g., erlotinib or bevacizumab) at the discretion of the oncologist. NOTE: *Patients whose imaging studies suggest potential curative resection are referred for a surgical evaluation before initiating gemcitabine hydrochloride therapy. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional patients are treated at the recommended phase II dose.

Patients are followed at 4 weeks and then every 8 weeks thereafter.

PROJECTED ACCRUAL: Approximately 3-46 patients will be accrued for this study within 2 years.

  Eligibility

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

Inclusion Criteria:

  • Histologically or cytologically confirmed adenocarcinoma of the pancreas

    • No non-adenocarcinoma of the pancreas (i.e., islet cell, lymphoma, or sarcoma)
    • Locally advanced and unresectable disease defined as the following:

      • Obvious encasement of the celiac, hepatic, or superior mesenteric artery
      • Encasement of the portal or superior mesenteric vein not amenable to resection
      • Extrapancreatic extension with or without regional lymph node involvement
      • No distant metastases
  • Measurable or evaluable disease

    • Primary pancreatic tumor is considered evaluable, not measurable
    • A lymph node mass is considered measurable
  • Performance status - ECOG 0-2
  • Performance status - Karnofsky 60-100%
  • More than 12 weeks
  • WBC at least 3,000/mm^3
  • Absolute neutrophil count at least 1,500/mm^3
  • Platelet count at least 100,000/mm^3
  • Bilirubin no greater than 1.5 mg/dL
  • AST and ALT no greater than 2.5 times upper limit of normal
  • Creatinine no greater than 1.5 mg/dL
  • Creatinine clearance at least 60 mL/min
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • No Crohn's disease or inflammatory bowel disease that would preclude study participation
  • No gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation
  • No other uncontrolled concurrent illness that would preclude study participation
  • No ongoing or active infection
  • No psychiatric illness or social situation that would preclude study participation
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No prior chemotherapy for this disease except gemcitabine hydrochloride-based therapy for which no radiologic evidence of distant metastatic disease exists
  • No prior flavopiridol or other cyclin-dependent kinase therapies
  • No prior radiotherapy for this disease
  • Prior curative surgery with local recurrence allowed
  • No other concurrent investigational therapy
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  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: NCT00047307

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: Gary K. Schwartz Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00047307     History of Changes
Other Study ID Numbers: NCI-2012-01430, 02-057, NCI-5764, MSKCC-02057, CDR0000257662, U01CA069856, R01CA067819
Study First Received: October 3, 2002
Last Updated: June 3, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Pancreatic Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gemcitabine
Alvocidib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Growth Inhibitors
Growth Substances
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014