Docetaxel, Oxaliplatin, and Fluorouracil in Treating Patients With Metastatic or Unresectable Stomach Cancer, Gastroesophageal Junction Cancer, or Other Solid Tumor

• ClinicalTrials.gov Identifier: NCT00711243
• Recruitment Status: Completed
• First Posted: July 8, 2008
• Results First Posted: October 26, 2018
• Last Update Posted: February 26, 2019
• Sponsor: Northwestern University
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Northwestern University

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as docetaxel, oxaliplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of docetaxel when given with oxaliplatin and fluorouracil and to see how well they work in treating patients with metastatic or unresectable stomach cancer, gastroesophageal junction cancer, or other solid tumor.

Condition or disease	Intervention/treatment	Phase
Gastric Cancer; Unspecified Adult Solid Tumor, Protocol Specific	Drug: docetaxel; Drug: fluorouracil; Drug: oxaliplatin	Phase 1; Phase 2

Detailed Description:

OBJECTIVES:

Primary

• To establish the maximum tolerated dose of docetaxel when administered with oxaliplatin and fluorouracil in patients with metastatic or unresectable solid tumors. (Phase I)
• To determine the response rate in patients with metastatic or unresectable adenocarcinoma of the stomach or gastroesophageal junction treated with this regimen. (Phase II)

Secondary

• To determine the dose limiting toxicity of this regimen in these patients.
• To evaluate the frequency of CYP3A4, CYP3A5, and MDR polymorphisms and their impact on toxicity of docetaxel.
• To evaluate the frequency of XRCC1 and ERCC2 polymorphisms and their impact on the toxicity of oxaliplatin.
• To evaluate the frequency of DPD and TSER polymorphisms and their impact on the toxicity of fluorouracil.
• To characterize the toxicity profile of this regimen in these patients.

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

Patients receive docetaxel IV over 1 hour and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 14 days for at least 2 courses in the absence of disease progression, symptomatic tumor progression, or unacceptable toxicity.

Patients undergo blood sample collection periodically for pharmacokinetic and pharmacogenomic correlative studies. Plasma concentrations of docetaxel are analyzed by reverse-phase high performance liquid chromatography and tandem mass spectrometry. Polymorphisms in CYP3A4/5, MDR, and other genes are analyzed by PCR.

After completion of study therapy, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 73 patients (30 for phase I and 43 for phase II) will be accrued for this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 59 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Taxotere, Oxaliplatin, and 5- Fluorouracil
• Actual Study Start Date: April 20, 2005
• Actual Primary Completion Date: December 15, 2008
• Actual Study Completion Date: February 25, 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1a; Docetaxel 25 mg/m2 + oxaliplatin 85 mg/m2 + 5-Fluorouracil 2.4 gm/m2	Drug: docetaxel; Docetaxel at the dose indicated by the patient cohort, administered intravenously in 5% dextrose over 1 hour on day 1 of each cycle.; Drug: fluorouracil; Intravenous infusion at 85 mg/m2 continuously over 46 hours beginning each cycle after docetaxel administration.; Drug: oxaliplatin; Oxaliplatin 2.4 gm/m2 administered intravenously in 5% dextrose over 2 hours each cycle beginning immediately following docetaxel
Experimental: Cohort 2a; Docetaxel 30 mg/m2 + oxaliplatin 85 mg/m2 + 5-Fluorouracil 2.4 gm/m2	Drug: docetaxel; Docetaxel at the dose indicated by the patient cohort, administered intravenously in 5% dextrose over 1 hour on day 1 of each cycle.; Drug: fluorouracil; Intravenous infusion at 85 mg/m2 continuously over 46 hours beginning each cycle after docetaxel administration.; Drug: oxaliplatin; Oxaliplatin 2.4 gm/m2 administered intravenously in 5% dextrose over 2 hours each cycle beginning immediately following docetaxel
Experimental: Cohort 3a; Docetaxel 40 mg/m2 + oxaliplatin 85 mg/m2 + 5-Fluorouracil 2.4 gm/m2	Drug: docetaxel; Docetaxel at the dose indicated by the patient cohort, administered intravenously in 5% dextrose over 1 hour on day 1 of each cycle.; Drug: fluorouracil; Intravenous infusion at 85 mg/m2 continuously over 46 hours beginning each cycle after docetaxel administration.; Drug: oxaliplatin; Oxaliplatin 2.4 gm/m2 administered intravenously in 5% dextrose over 2 hours each cycle beginning immediately following docetaxel
Experimental: Cohort 4a; Docetaxel 50 mg/m2 + oxaliplatin 85 mg/m2 + 5-Fluorouracil 2.4 gm/m2	Drug: docetaxel; Docetaxel at the dose indicated by the patient cohort, administered intravenously in 5% dextrose over 1 hour on day 1 of each cycle.; Drug: fluorouracil; Intravenous infusion at 85 mg/m2 continuously over 46 hours beginning each cycle after docetaxel administration.; Drug: oxaliplatin; Oxaliplatin 2.4 gm/m2 administered intravenously in 5% dextrose over 2 hours each cycle beginning immediately following docetaxel
Experimental: Cohort 5a; Docetaxel 60 mg/m2 + oxaliplatin 85 mg/m2 + 5-Fluorouracil 2.4 gm/m2	Drug: docetaxel; Docetaxel at the dose indicated by the patient cohort, administered intravenously in 5% dextrose over 1 hour on day 1 of each cycle.; Drug: fluorouracil; Intravenous infusion at 85 mg/m2 continuously over 46 hours beginning each cycle after docetaxel administration.; Drug: oxaliplatin; Oxaliplatin 2.4 gm/m2 administered intravenously in 5% dextrose over 2 hours each cycle beginning immediately following docetaxel

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of Docetaxel When Given in Combination With Oxaliplatin and Fluorouracil (Phase I) [ Time Frame: After completion of 1 cycle of therapy (1 cycle = 14 days) ]

   The MTD will be determined using a 3+3 dose escalating design. There will be 5 dose cohorts:

   Cohort 1a 25mg/m2 Cohort 2a 30mg/m2 Cohort 3a 40 mg/m2 Cohort 4a 50 mg/m2 Cohort 5a 60 mg/m2

   3 patients will be enrolled at dose of 25mg/m2 docetaxel. If no dose limiting toxicities (DLTs) are seen then dose will be escalated to next cohort and 3 patients will be treated at that dose level. If a DLT is seen at any dose, then 3 more patients will be enrolled at that dose level. If 1 patient out of 6, experience a DLT then MTD will be determined to be at this dose level. If 2 or more DLTs are seen in first 3 patients at that dose, then MTD will be one dose lower to the level where the DLTs were experienced. Dose of docetaxel will be escalated by use of cohorts until the MTD for phase II is determined.

   DLTs were defined using the National Cancer Institute Common Toxicity Criteria Version 3.0

2. Response Rate in Patients With Adenocarcinoma of the Stomach or Gastroesophageal Junction (Phase II) [ Time Frame: After 4 cycles of therapy (1 cycle = 14 days) ]

   Overall Response Rate (ORR) is defined as Complete Response (CR) plus Partial Response (PR) and will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan.

   Complete Response (CR) - Disappearance of all target lesions. Partial Response (PR), >=30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum.

   Stable Disease, neither sufficient shrinkage to qualify for Partial disease nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD while on study.

   Progressive Disease - <=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures :

1. Dose-limiting Toxicity of Docetaxel When Given in Combination With Oxaliplatin and Fluorouracil [ Time Frame: After 1 cycle of therapy (1 cycle = 14 days) ]

   Dose limiting toxicities (DLT) will be graded according to National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0) except for neurosensory. The occurrence of any of the following during the 1st cycle, seen in more than one patient, will constitute a DLT.

   Grade 3 non-hematologic toxicity(except alopecia) Grade 4 thrombocytopenia, not recovered to platelet count of >75,000/ul by day 15.

   Grade 4 neutropenia, not recovered to count of >1,500/ul by day 15. Grade 4 neutropenia with fever or infection. Grade 2 neurologic-sensory toxicity not recovered to grade 1 or better by day 15

2. Frequency of CYP3A4, CYP3A5, and MDR Polymorphisms and Their Impact on Docetaxel Toxicity [ Time Frame: Blood sample cycle 1 day 1 and toxicity on day 1 of each cycle ]
3. Frequency of XRCC1 and ERCC2 Polymorphisms and Their Impact on Oxaliplatin Toxicity [ Time Frame: Blood sample cycle 1 day 1 and toxicity on day 1 of each cycle ]
4. Frequency of DPD and TSER Polymorphisms and Their Impact on Fluorouracil Toxicity [ Time Frame: Blood sample cycle 1 day 1 and toxicity on day 1 of each cycle ]
5. Toxicity Profile [ Time Frame: Day 1 of each cycle of therapy with 1 cycle =14 days until disease progression for up to a maximum of 34 cycles and 30 days after last treatment ]

   Toxicity data will be collected on day 1 of every 14 day cycle during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events (AE) version 3.0 (CTCAE v3.0). For patients that experience multiple grades of the same AE that is determined to be at least possibly related to at least one study drug, only highest grade will be collected. In general AEs will be graded according to the following:

   Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic or surgically unresectable solid tumor meeting 1 of the following criteria:

  • Any solid tumor (Phase I)
  • Adenocarcinoma of the stomach or gastroesophageal junction (Phase II)
• Unidimensionally measurable disease by CT scan or MRI
• No uncontrolled brain metastasis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8.0 g/dL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Total bilirubin normal

• Meets 1 of the following criteria:

  • Alkaline phosphatase (AP) normal AND AST or ALT ≤ 5 times ULN
  • AP ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN
  • AP ≤ 5 times ULN AND AST or ALT normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 3 months after completion of study therapy
• No preexisting neuropathy
• No concurrent uncontrolled illness or other condition that would preclude study compliance
• No history of severe hypersensitivity reaction to docetaxel or to other drugs formulated with polysorbate 80
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in this study

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• More than 4 weeks since prior therapy (Phase I)
• No prior oxaliplatin or taxanes (Phase I)
• More than 4 weeks since prior radiotherapy (Phase I)
• No more than two prior therapies for metastatic disease (Phase I)
• No prior therapy for metastatic disease (Phase II)
• At least 6 months since prior adjuvant therapy (given prior to the occurrence of metastatic disease) (Phase II)
• Prior fluorouracil and concurrent radiotherapy for palliation of the primary tumor allowed provided metastatic disease is present outside the radiotherapy field (Phase II)
• No prior radiotherapy to ≥ 30% of bone marrow
• No other concurrent investigational agents

Contacts and Locations

Locations

United States, Illinois

Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Chicago, Illinois, United States, 60611-3013

Sponsors and Collaborators

Northwestern University

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mary Mulcahy, MD; Robert H. Lurie Cancer Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rosenberg AJ, Rademaker A, Hochster HS, Ryan T, Hensing T, Shankaran V, Baddi L, Mahalingam D, Mulcahy MF, Benson AB 3rd. Docetaxel, Oxaliplatin, and 5-Fluorouracil (DOF) in Metastatic and Unresectable Gastric/Gastroesophageal Junction Adenocarcinoma: A Phase II Study with Long-Term Follow-Up. Oncologist. 2019 Aug;24(8):1039-e642. doi: 10.1634/theoncologist.2019-0330. Epub 2019 May 28.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT00711243
• Other Study ID Numbers: NU 04I2; P30CA060553 ( U.S. NIH Grant/Contract ); NU-0412; SANOFI - AVENTIS-NU0412; NU-948-006; STU00006778 ( Other Identifier: Northwestern University IRB )
• First Posted: July 8, 2008
• Results First Posted: October 26, 2018
• Last Update Posted: February 26, 2019
• Last Verified: October 2018

Keywords provided by Northwestern University:

unspecified adult solid tumor, protocol specific; adenocarcinoma of the stomach; stage III gastric cancer; stage IV gastric cancer

Additional relevant MeSH terms:

Stomach Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Docetaxel; Fluorouracil; Oxaliplatin; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs