Combined Modality Therapy for Patients With With HIV and Stage I, Stage II, or Stage III Anal Cancer

• Sponsor: AIDS Malignancy Consortium (Other)
• Overall Status: Completed
• CT.gov ID: NCT00324415
• Collaborator: National Cancer Institute (NCI) (NIH), The Emmes Company, LLC (Industry)
• Enrollment: 45
• Locations: 7
• Arm: 1
• Duration (Months): 116
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving cisplatin, fluorouracil, and cetuximab together with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving cisplatin, fluorouracil, and cetuximab together with radiation therapy works in treating patients with HIV and stage I, stage II, or stage III anal cancer.

Condition or Disease	Intervention/Treatment	Phase
Anal Cancer	Biological: cetuximab; Drug: cisplatin; Drug: fluorouracil; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the 2-year local failure rate in patients with HIV-associated stage I-IIIB anal carcinoma treated with cisplatin, fluorouracil, cetuximab, and radiotherapy.

• Determine the objective response rate (complete and partial), progression-free survival, relapse-free survival, colostomy-free survival, overall survival, quality of life, and overall toxicity in patients treated with this regimen.

Secondary

• Characterize the effect of this regimen on the underlying HIV condition by describing changes in viral load, CD4 counts, and the incidence of opportunistic illnesses, including the development of AIDS during and in the first year after treatment.

• Evaluate the effect of this regimen on anogenital human papilloma virus (HPV) infection and anal cytology.

OUTLINE: This is an open-label, multicenter study.

Patients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 35*, fluorouracil IV continuously on days 1-4 and 29-32, and cisplatin IV over 1 hour on days 1 and 29. Beginning on day 1, patients undergo concurrent radiotherapy to the primary tumor 5 days a week for 5-7 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients receiving 7 weeks of radiotherapy also receive cetuximab on days 42 and 49.

Quality of life is assessed at baseline, at the completion of study treatment, and then at months 3, 6, 12, 24, and 36.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Combined Modality Therapy Plus Cetuximab in HIV-Associated Anal Carcinoma
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: CMT with Radiation Therapy All patients will receive combined modality therapy (CMT) with 2 cycles of cisplatin and 5-FU chemotherapy, given concurrently with radiation therapy. CMT consists of: Cetuximab 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose). Cisplatin 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2) 5-FU 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2)

Biological: cetuximab; 400 mg/m2 IV Day -7 (1 week before the cycle 1, Day 1 cisplatin/5-FU and RT), then 250 mg/m2 IV Days 1, 8, 15, 22, 29, 36 and 43 (a minimum of 6 and a maximum of 8 doses of cetuximab will be administered, including the loading dose); Other Names: Erbitux ; Drug: cisplatin; 75 mg/m2 IV on Day 1 (cycle 1) and Day 29 (cycle 2); Other Names: Platinol ; Drug: fluorouracil; 1000 mg/m2/day by continuous intravenous infusion on Days 1-4 (cycle 1) and Days 29-32 (cycle 2); Other Names: 5-FU Adrucil Carac Efudex Fluoroplex ; Radiation: radiation therapy; Irradiation to tumor site and inguinal nodes beginning on cycle 1, Day 1 cisplatin/5-FU (minimum 45.0 Gy [5 weeks if given on schedule and without interruption], maximum 54.0 Gy [6 weeks if given on schedule and without interruption). IMRT may be used at the discretion of the treating physician.

Outcome Measures

Primary Outcome Measures

1. Local Failure Rate at 3 Years [3 years following treatment discontinuation]

   Patients will be classified into two groups for purposes of primary endpoint analysis: failure or no failure at 3 years (in the primary analysis, patients lost to follow-up prior to 3 years will be considered failures). For the secondary endpoint of objective response, patients will be classified as responders

Secondary Outcome Measures

1. Progression-free Survival [1 year]

   Progression-free survival at 1 year is the percentage of patients who are alive and have not experienced progressive disease, defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one or more new lesions.

2. Relapse-free Survival [1 year]

   Percentage of participants who are alive and have not experienced progressive disease and have not relapsed

3. Colostomy-free Survival at 1 Year [1 year]

   Percentage of participants who are alive and have not had a colostomy

4. Overall Survival [1 year]

   Percentage of participants who are alive at one year

5. Quality of Life [1 year]

   EORTC QLQ-C30 Global Score at 1 year. The EORTC QLQ-C30 is a validated questionnaire that evaluates quality of life. The global score is an overall score for quality of life that ranges from 0 to 100. Higher scores indicate between quality of life

6. Toxicity [90 days following treatment discontinuation]

   Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion

7. Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment [1 year following treatment discontinuation]

   Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment

8. Incidence of Opportunistic Illnesses [1 year following treatment discontinuation]

   Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment

9. Anogenital Human Papilloma Virus (HPV) Infection and Anal Cytology [6 months following treatment discontinuation]

10. Objective Response Rate (Complete and Partial) [3 years following treatment discontinuation]

    Number of participants with complete and partial responses based on the RECIST criteria

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed stage I-IIIB invasive anal canal or perianal (anal margin) squamous cell carcinoma, including tumors with any of the following nonkeratinizing histologies:

• Basaloid

• Transitional cell

• Cloacogenic

• Documented HIV infection by 1 of the following:

• Antibody detection

• Culture

• Quantitative assay of plasma HIV RNA

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 10 g/dL (transfusions, epoetin alfa, or myeloid growth factor support allowed provided blood counts are stable for ≥ 2 weeks prior to study entry)

• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance > 60 mL/min

• AST and ALT ≤ 3 times ULN

• Bilirubin ≤ 2 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No acute active, serious, uncontrolled opportunistic infection

• No other prior invasive malignancy diagnosed within the past 24 months, excluding in situ cervical cancer, anal dysplasia or carcinoma in situ, nonmelanoma skin carcinoma, or Kaposi's sarcoma that has not required systemic chemotherapy within the past 24 months

• No peripheral neuropathy > grade 1

• No severe or poorly controlled diarrhea

• No medical or psychiatric illness that would preclude study requirements

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy for this malignancy

• Prior radiotherapy for another condition (e.g., Kaposi's sarcoma) allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	UCLA Clinical AIDS Research and Education (CARE) Center	Los Angeles	California	United States	90095-1793
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
4	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
5	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
6	Joan Karnell Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19106
7	Benaroya Research Institute at Virginia Mason Medical Center	Seattle	Washington	United States	98101

Sponsors and Collaborators

• AIDS Malignancy Consortium
• National Cancer Institute (NCI)
• The Emmes Company, LLC

Investigators

• Study Chair: Joseph A. Sparano, MD, Albert Einstein College of Medicine
• Principal Investigator: Lisa A. Kachnic, MD, Massachusetts General Hospital
• Principal Investigator: David M. Aboulafia, MD, Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 30, 2014

More Information

Publications

None provided.

• Responsible Party: AIDS Malignancy Consortium
• ClinicalTrials.gov Identifier: NCT00324415
• Other Study ID Numbers: AMC-045; U01CA070019; CDR0000440065
• First Posted: May 11, 2006
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by AIDS Malignancy Consortium: stage I anal cancer; stage II anal cancer; stage IIIA anal cancer; stage IIIB anal cancer; squamous cell carcinoma of the anus; basaloid carcinoma of the anus; cloacogenic carcinoma of the anus
• Additional relevant MeSH terms: Anus Neoplasms; Fluorouracil; Cetuximab

Study Results

Participant Flow

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	Combined modality therapy consists of cisplatin, 5-flourouracil, and irradiation plus cetuximab
Period Title: Overall Study
STARTED	45
COMPLETED	45
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Overall Participants	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.4 (6.7)
Sex: Female, Male (Count of Participants)
Female	4 8.9%
Male	41 91.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 15.6%
Not Hispanic or Latino	37 82.2%
Unknown or Not Reported	1 2.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	13 28.9%
White	28 62.2%
More than one race	0 0%
Unknown or Not Reported	4 8.9%
Region of Enrollment (participants) [Number]
United States	45 100%

Outcome Measures

1. Primary Outcome

Title	Local Failure Rate at 3 Years
Description	Patients will be classified into two groups for purposes of primary endpoint analysis: failure or no failure at 3 years (in the primary analysis, patients lost to follow-up prior to 3 years will be considered failures). For the secondary endpoint of objective response, patients will be classified as responders
Time Frame	3 years following treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Measure Participants	45
Number [participants]	23 51.1%

2. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival at 1 year is the percentage of patients who are alive and have not experienced progressive disease, defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, or the appearance of one or more new lesions.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	87.3 194%

3. Secondary Outcome

Title	Relapse-free Survival
Description	Percentage of participants who are alive and have not experienced progressive disease and have not relapsed
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	83.1 184.7%

4. Secondary Outcome

Title	Colostomy-free Survival at 1 Year
Description	Percentage of participants who are alive and have not had a colostomy
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	92.4 205.3%

5. Secondary Outcome

Title	Overall Survival
Description	Percentage of participants who are alive at one year
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	92.8 206.2%

6. Secondary Outcome

Title	Quality of Life
Description	EORTC QLQ-C30 Global Score at 1 year. The EORTC QLQ-C30 is a validated questionnaire that evaluates quality of life. The global score is an overall score for quality of life that ranges from 0 to 100. Higher scores indicate between quality of life
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The number of participants analyzed is the number of participants for whom quality of life questionnaires were completed at one year.

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
Measure Participants	29
Mean (Standard Deviation) [units on a scale]	78.9 (24.0)

7. Secondary Outcome

Title	Toxicity
Description	Delayed toxicities are defined as toxicities that occur over 90 days following treatment completion
Time Frame	90 days following treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
Measure Participants	45
Number [events]	5

8. Secondary Outcome

Title	Changes in CD4 Counts During and for 1 Year After Completion of Study Treatment
Description	Change in absolute CD4 counts from start of treatment to 1 year after completion of study treatment
Time Frame	1 year following treatment discontinuation

Outcome Measure Data

Analysis Population Description

The number of participants analyzed is the number for whom absolute CD4 count data were available at baseline at at 1 year after study completion

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
Measure Participants	38
Median (Full Range) [cells/mm3]	102

9. Secondary Outcome

Title	Incidence of Opportunistic Illnesses
Description	Incidence of opportunistic illnesses, including the development of AIDS during and for 1 year after completion of study treatment
Time Frame	1 year following treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
Measure Participants	45
Number [participants]	4 8.9%

10. Secondary Outcome

Title	Anogenital Human Papilloma Virus (HPV) Infection and Anal Cytology
Time Frame	6 months following treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Objective Response Rate (Complete and Partial)
Description	Number of participants with complete and partial responses based on the RECIST criteria
Time Frame	3 years following treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
Measure Participants	45
Number [participants]	30 66.7%

Adverse Events

Time Frame	3 years
Arm/Group Title	Combined Modality Therapy
Arm/Group Description	cisplatin, 5-flourouruacil, and irradiation plus cetuximab
All Cause Mortality
	Combined Modality Therapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combined Modality Therapy
	Affected / at Risk (%)	# Events
Total	27/45 (60%)
Blood and lymphatic system disorders
Anemia	2/45 (4.4%)	2
Febrile neutropenia	3/45 (6.7%)	3
Gastrointestinal disorders
Anal fistula	2/45 (4.4%)	2
Anal mucositis	1/45 (2.2%)	1
Anal pain	3/45 (6.7%)	3
Diarrhea	8/45 (17.8%)	9
Duodenal hemorrhage	1/45 (2.2%)	1
Enterocolitis	1/45 (2.2%)	1
Esophagitis	1/45 (2.2%)	1
Gastritis	1/45 (2.2%)	1
Oral mucositis	1/45 (2.2%)	1
Nausea	3/45 (6.7%)	3
Vomiting	2/45 (4.4%)	2
melena	1/45 (2.2%)	1
General disorders
death NOS	3/45 (6.7%)	3
Fatigue	1/45 (2.2%)	1
Fever	2/45 (4.4%)	2
Pain	1/45 (2.2%)	1
Infections and infestations
Anorectal infection	3/45 (6.7%)	3
Lung infection	1/45 (2.2%)	1
Meningitis	1/45 (2.2%)	1
Scrotal infection	1/45 (2.2%)	1
Wound infection	1/45 (2.2%)	1
Infection with grade 3 or 4 neutrophils	2/45 (4.4%)	2
Lung pneumonia	1/45 (2.2%)	1
Toxoplasmosis with Hydrocephalus	1/45 (2.2%)	1
Cellulitis	1/45 (2.2%)	1
Injury, poisoning and procedural complications
Fracture	1/45 (2.2%)	1
Radiation reaction (dermatologic)	1/45 (2.2%)	1
Investigations
Creatinine increased	1/45 (2.2%)	1
Neutrophil count decreased	3/45 (6.7%)	3
Platelet count decreased	3/45 (6.7%)	3
White blood count decreased	3/45 (6.7%)	3
Metabolism and nutrition disorders
Acidosis	1/45 (2.2%)	1
Anorexia	1/45 (2.2%)	1
Dehydration	9/45 (20%)	9
Hypokalemia	9/45 (20%)	9
Pain in extremity	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	1/45 (2.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/45 (2.2%)	1
Nervous system disorders
Cognitive disturbance	2/45 (4.4%)	2
Headache	1/45 (2.2%)	1
Syncope	1/45 (2.2%)	1
Renal and urinary disorders
Acute kidney injury	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/45 (2.2%)	1
Respiratory arrest	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	1/45 (2.2%)	1
Other skin disorder	2/45 (4.4%)	2
Vascular disorders
Hypotension	1/45 (2.2%)	1
Thromboembolic event	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Combined Modality Therapy
	Affected / at Risk (%)	# Events
Total	41/45 (91.1%)
Blood and lymphatic system disorders
Anemia	14/45 (31.1%)	26
Other blood and lymphatic disorders	5/45 (11.1%)	7
Gastrointestinal disorders
Abdominal pain	3/45 (6.7%)	3
Constipation	7/45 (15.6%)	7
Anal pain	10/45 (22.2%)	14
Diarrhea	22/45 (48.9%)	38
Other GI disorders	9/45 (20%)	21
Oral mucositis	10/45 (22.2%)	23
Nausea	12/45 (26.7%)	18
Proctitis	5/45 (11.1%)	7
Rectal pain	3/45 (6.7%)	4
Vomiting	7/45 (15.6%)	8
General disorders
Fatigue	17/45 (37.8%)	18
Fever	5/45 (11.1%)	5
Other general disorders	6/45 (13.3%)	7
Pain	3/45 (6.7%)	4
Infections and infestations
Anorectal infection	3/45 (6.7%)	3
Other infections	4/45 (8.9%)	6
Injury, poisoning and procedural complications
Dermatitis radiation	3/45 (6.7%)	3
Radiation recall reaction (dermatologic)	11/45 (24.4%)	16
Aspartate aminotransferase increased	4/45 (8.9%)	4
Investigations
Alanine aminotransferase increased	4/45 (8.9%)	4
Blood bilirubin increased	3/45 (6.7%)	6
Neutrophil count decreased	10/45 (22.2%)	18
Platelet count decreased	13/45 (28.9%)	17
Weight loss	11/45 (24.4%)	12
White blood cell decreased	11/45 (24.4%)	34
Metabolism and nutrition disorders
Anorexia	9/45 (20%)	11
Dehydration	10/45 (22.2%)	11
hypoalbuminemia	4/45 (8.9%)	5
Hypocalcemia	7/45 (15.6%)	9
Hypokalemia	10/45 (22.2%)	17
Hypomagnesia	5/45 (11.1%)	5
Hyponatremia	7/45 (15.6%)	11
Musculoskeletal and connective tissue disorders
Muscle weakness	3/45 (6.7%)	3
Nervous system disorders
Anxiety	3/45 (6.7%)	3
Depression	4/45 (8.9%)	4
Insomnia	4/45 (8.9%)	4
Renal and urinary disorders
Other renal and urinary disorders	3/45 (6.7%)	4
Respiratory, thoracic and mediastinal disorders
Cough	3/45 (6.7%)	3
Dyspnea	6/45 (13.3%)	6
Skin and subcutaneous tissue disorders
Alopecia	5/45 (11.1%)	5
Dry skin	4/45 (8.9%)	4
Erythema multiforme	3/45 (6.7%)	3
Rash acneiform	12/45 (26.7%)	15
Other skin disorders	12/45 (26.7%)	20
Skin ulceration	3/45 (6.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.