S0304 Induct Chemo Then Chemo-RT in Pts w/Locally Advanced Adenocarcinoma of the Rectum

Sponsor

Southwest Oncology Group (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00070434

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Arms

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as irinotecan, leucovorin, fluorouracil, and oxaliplatin, use 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. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well different regimens of induction chemotherapy followed by chemoradiotherapy work in treating patients with locally advanced adenocarcinoma of the rectum.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: capecitabine Drug: fluorouracil Drug: irinotecan hydrochloride Drug: leucovorin calcium Drug: oxaliplatin Radiation: radiation therapy Drug: Pyridoxine	Phase 2

Detailed Description

OBJECTIVES:

Determine the feasibility of obtaining a pre-treatment determination of intratumoral molecular markers (TS, DPD, and ERCC-1) for use in selection of the appropriate regimen for induction cytotoxic combination chemotherapy in patients with cT3-4 rectal adenocarcinoma.
Determine the response probability (unconfirmed, complete and partial) in patients treated with targeted induction cytotoxic chemotherapy.
Determine the toxicity of targeted induction cytotoxic chemotherapy and chemoradiotherapy in these patients.
Determine the response probability in these patients treated with chemoradiotherapy.

OUTLINE: This is a multicenter study.

Induction chemotherapy: Patients are assigned to 1 of 3 treatment groups based on molecular analysis of the pretreatment tumor specimen.
Group I (lower likelihood of resistance to a fluorouracil-based regimen): Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1.
Group II (higher likelihood of resistance to a fluorouracil-based regimen): Patients receive oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on day 1.
Group III (high likelihood of sensitivity to oxaliplatin and fluorouracil therapy): Patients receive oxaliplatin IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours beginning on day 1.

Treatment in all groups repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients are evaluated for response approximately 2 weeks after the completion of induction chemotherapy. Patients with stable disease or better receive chemoradiotherapy.

Chemoradiotherapy: Beginning approximately 3 weeks after the completion of induction chemotherapy, patients receive oral capecitabine twice daily continuously for 5 weeks and concurrent radiotherapy once daily 5 days a week for 5 weeks.

After chemoradiotherapy, patients may undergo attempted surgical resection at the discretion of the treating physician.

Patients are followed every 3 months for 1 year and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 10-65 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Feasibility Translational Research Trial of Induction Chemotherapy Followed by Concomitant Chemoradiation in Patients With Clinical T4 Rectal Cancer

Study Start Date :

Aug 1, 2004

Actual Primary Completion Date :

Feb 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Irinotecan + 5-FU + Leucovorin Irinotecan 180mg/m2, IV for 90min on Day 1, q 2 wk x 4 cycles; 5-FU 400 mg/m2, IV bolus on Day 1, q 2 wk x 4 cycles; 5-FU 2.4 g/m2 IV for 46 hours on Day 1, q 2 wk x 4 cycles; Leucovorin 200 mg/m2 IV for 2 hours on Day 1, q 2 wk x4 cycles.	Drug: capecitabine 825mg/m2 BID, PO, daily Drug: fluorouracil Bolus + IV for 46 hrs on Day 1 Drug: irinotecan hydrochloride IV infusion over 90 min on Day 1 Drug: leucovorin calcium 200mg/m2 IV 2 hour infusion on Day 1 Radiation: radiation therapy Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily. Drug: Pyridoxine 50mg TID, PO daily
Experimental: Irinotecan + Oxaliplatin Irinotecan 175mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; Oxaliplatin 85mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles	Drug: capecitabine 825mg/m2 BID, PO, daily Drug: irinotecan hydrochloride IV infusion over 90 min on Day 1 Drug: oxaliplatin 85mg/m2 IV infusion for 90minutes on Day 1 Radiation: radiation therapy Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily. Drug: Pyridoxine 50mg TID, PO daily
Experimental: Oxaliplatin + 5-FU + Leucovorin Oxaliplatin 85mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; 5-FU 400mg/m2 IV bolus on Day 1, q 2wk x4 cycles; 5-FU 2.4g/m2 IV for 46 hours on Day 1, q 2wk x4 cycles; Leucovorin 200mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles.	Drug: capecitabine 825mg/m2 BID, PO, daily Drug: fluorouracil Bolus + IV for 46 hrs on Day 1 Drug: leucovorin calcium 200mg/m2 IV 2 hour infusion on Day 1 Drug: oxaliplatin 85mg/m2 IV infusion for 90minutes on Day 1 Radiation: radiation therapy Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily. Drug: Pyridoxine 50mg TID, PO daily

Arm

Intervention/Treatment

Experimental: Irinotecan + 5-FU + Leucovorin

Irinotecan 180mg/m2, IV for 90min on Day 1, q 2 wk x 4 cycles; 5-FU 400 mg/m2, IV bolus on Day 1, q 2 wk x 4 cycles; 5-FU 2.4 g/m2 IV for 46 hours on Day 1, q 2 wk x 4 cycles; Leucovorin 200 mg/m2 IV for 2 hours on Day 1, q 2 wk x4 cycles.

Drug: capecitabine

825mg/m2 BID, PO, daily

Drug: fluorouracil

Bolus + IV for 46 hrs on Day 1

Drug: irinotecan hydrochloride

IV infusion over 90 min on Day 1

Drug: leucovorin calcium

200mg/m2 IV 2 hour infusion on Day 1

Radiation: radiation therapy

Original Planning Target Volume (PTV1): The total dose to the prescription point shall be 4500 cGy in 25 fractions (Monday - Friday inclusive). Boost Planning Target Volume (PTV2): The cumulative dose within the boost volume to the prescription point shall be 5,040 - 5,400 cGy (per Section 7.5b). Daily Dose: The daily dose to the prescription point of the original and boost volumes shall be 180 cGy. Fractionation: Treatment shall be given 5 days/week. All radiation fields shall be treated once daily.

Drug: Pyridoxine

50mg TID, PO daily

Experimental: Irinotecan + Oxaliplatin

Irinotecan 175mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; Oxaliplatin 85mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles

Drug: capecitabine

825mg/m2 BID, PO, daily

Drug: irinotecan hydrochloride

IV infusion over 90 min on Day 1

Drug: oxaliplatin

85mg/m2 IV infusion for 90minutes on Day 1

Radiation: radiation therapy

Drug: Pyridoxine

50mg TID, PO daily

Experimental: Oxaliplatin + 5-FU + Leucovorin

Oxaliplatin 85mg/m2 IV for 90 minutes on Day 1, q 2wk x4 cycles; 5-FU 400mg/m2 IV bolus on Day 1, q 2wk x4 cycles; 5-FU 2.4g/m2 IV for 46 hours on Day 1, q 2wk x4 cycles; Leucovorin 200mg/m2 IV for 2 hours on Day 1, q 2wk x4 cycles.

Drug: capecitabine

825mg/m2 BID, PO, daily

Drug: fluorouracil

Bolus + IV for 46 hrs on Day 1

Drug: leucovorin calcium

200mg/m2 IV 2 hour infusion on Day 1

Drug: oxaliplatin

85mg/m2 IV infusion for 90minutes on Day 1

Radiation: radiation therapy

Drug: Pyridoxine

50mg TID, PO daily

Outcome Measures

Primary Outcome Measures

Response (confirmed and unconfirmed response, complete response, partial response) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed primary adenocarcinoma of the rectum
Locally advanced disease (clinical T3-4, N0-2, M0) based on at least 1 of the following criteria:
Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall and/or sacrum
Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane is considered evidence of fixation
Hydronephrosis on CT scan or intravenous pyelogram of ureteric or bladder invasion by cystoscopy and cytology or biopsy
Invasion into the prostate, vagina, or uterus
Transmural penetration of tumor through the muscularis propria as evidenced by CT scan or MRI and endorectal ultrasound
Distal border of the tumor must be at or below the peritoneal reflection (within 12 cm of the anal verge) by proctoscopic examination
Measurable disease by x-ray, scans, or physical examination
Available tumor tissue to determine molecular profile of the tumor before study treatment
No clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction unless a diverting colostomy has been performed

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

Zubrod 0-2

Life expectancy

Not specified

Hematopoietic

WBC ≥ 3,500/mm^3
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥100,000/mm^3

Hepatic

Bilirubin ≤ 1.5 times upper limit of normal (ULN)
SGOT or SGPT ≤ 2.5 times ULN
Alkaline phosphatase ≤ 2.5 times ULN

Renal

See Disease Characteristics
Creatinine ≤ 1.5 times ULN OR
Estimated creatinine clearance > 50 mL/min

Cardiovascular

No significant cardiac disease
No recent myocardial infarction

Gastrointestinal

See Disease Characteristics
Able to swallow oral medication
No active inflammatory bowel disease

Other

Not pregnant or nursing
Fertile patients must use effective contraception
No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
No prior unanticipated severe reaction to study drugs
No known dihydropyrimidine dehydrogenase deficiency
No serious uncontrolled infection
No other serious medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

No prior chemotherapy for colon or rectal cancer

Endocrine therapy

Not specified

Radiotherapy

No prior pelvic radiotherapy
No prior intra-operative radiotherapy or brachytherapy
No concurrent intra-operative radiotherapy or brachytherapy
No concurrent intensity-modulated radiotherapy

Surgery

See Disease Characteristics
See Radiotherapy

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Southwest Oncology Group
National Cancer Institute (NCI)

Investigators

Study Chair: Charles R. Thomas, MD, The University of Texas Health Science Center at San Antonio
Study Chair: Heinz-Josef Lenz, MD, University of Southern California
Study Chair: Robert P. Whitehead, MD, University of Texas
Study Chair: James L. Abbruzzese, MD, M.D. Anderson Cancer Center
Study Chair: Stephen R. Smalley, MD, Radiation Oncology Center of Olathe
Study Chair: Morton S. Kahlenberg, MD, The University of Texas Health Science Center at San Antonio