Neoplasms

All Conditions

Digestive System Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Anus Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Anal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive nivolumab while on study. Patients undergo sigmoidoscopy, colonoscopy or anoscopy, proctoscopy or digital rectal exam, x-ray, CT scan, MRI, biopsy and blood sample collection throughout the study.

Patients undergo observation while on study. Patients undergo sigmoidoscopy, colonoscopy or anoscopy, proctoscopy or digital rectal exam, x-ray, CT scan, MRI, biopsy and blood sample collection throughout the study.

Biopsy

Biospecimen Collection

Colonoscopy

Computed Tomography

Digital Rectal Examination

High Resolution Anoscopy

Magnetic Resonance Imaging

Patient Observation

Proctoscopy

Sigmoidoscopy

X-Ray Imaging

Lakshmi Rajdev

This phase III trial investigates how well nivolumab after combined modality therapy works in treating patients with high risk stage II-IIIB anal cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVE:

I. To evaluate whether therapy with nivolumab following combined modality therapy (CMT) improves disease-free survival (DFS) compared with observation in patients with high risk anal carcinoma.

SECONDARY OBJECTIVES:

I. To compare nivolumab following combined modality therapy (CMT) with observation in patients with high risk anal carcinoma with regard to:

Ia. Objective response rate (complete \[CR\] and partial \[PR\]), stable disease and progression.

Ib. Severe toxicity interval. Ic. Colostomy-free survival. Id. Overall survival. Ie. Toxicity.

OUTLINE: Patients who received standard CMT are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) while on study.

ARM B: Patients undergo observation while on study

Patients undergo sigmoidoscopy, colonoscopy or anoscopy, proctoscopy or digital rectal exam, x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), biopsy and blood sample collection throughout the study.

Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer

A Randomized Phase III Study of Nivolumab After Combined Modality Therapy (CMT) in High Risk Anal Cancer

Will be defined as the occurrence of progression of local disease, distant metastases, second primary or death from the date of randomization.

Will be defined by complete and partial response.

The following late side effects are considered as severe: any anal/rectal damage (ulcer, fistula, or perforation), rectal stenosis that required colostomy, skin ulceration, and severe fibrosis. This parameter estimates the probability of being free of late side effects for patients under loco-regional control.

Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Canadian Cancer Trials Group

National Cancer Institute (NCI)

Infections

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Communicable Diseases

Acquired Immunodeficiency Syndrome

HIV Infections

Anti-Infective Agents

Fluorouracil

Capecitabine

Mitomycins

Mitomycin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Enzyme Inhibitors

Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive mitomycin IV on day 1 and either fluorouracil IV on day 1 or capecitabine PO BID on Monday-Friday until the completion of radiation therapy at the discretion of the treating physician. Patients also undergo IMRT QD for 20-23 treatment sessions over 6 weeks.

Intensity-Modulated Radiation Therapy

Site Public Contact

Chia-Ching (Jackie) Wang

Sharad Goyal

Julian Sanchez

Yolande Chen

Lee Ratner

Rafi Kabarriti

Celina S. Ang

Patricia A. Locantore-Ford

This phase II trial studies the side effects of chemotherapy and intensity modulated radiation therapy in treating patients with low-risk HIV-associated anal cancer, and nivolumab after standard of care chemotherapy and radiation therapy in treating patients with high-risk HIV-associated anal cancer. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as mitomycin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with radiation therapy may kill more tumor cells. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab after standard of care chemotherapy and radiation therapy may help reduce the risk of the tumor coming back.

PRIMARY OBJECTIVES:

I. To determine the safety of reduced intensity chemo-radiation therapy (CRT) in low-risk disease.

II. To determine the safety of nivolumab after standard CRT in high-risk disease.

SECONDARY OBJECTIVES:

I. To estimate the efficacy (2-year disease-control rate \[DCR\]) of reduced intensity CRT in low risk disease.

II. To estimate the efficacy (2-year disease-free survival \[DFS\] rate) of nivolumab after standard CRT in high risk disease.

III. To evaluate the effect of low-dose CRT on immune function (CD4+ cell count) and human immunodeficiency virus (HIV) viral load.

IV. To evaluate the effect of nivolumab on immune function (CD4+ cell count) and HIV viral load.

V. To assess combination antiretroviral therapy (cART) adherence before, during, and after treatment with CRT and nivolumab to identify potential barriers to cART adherence when receiving concurrent oncological care.

EXPLORATORY OBJECTIVES:

I. To determine the human papillomavirus (HPV) genotype in primary tumor and explore the relationship between specific HPV subtypes and clinical response to reduced intensity CRT or nivolumab.

II. To explore the relationship between expression of PD-1 in immune cells and PD-L1 in immune cells or cancer epithelial cells in the primary diagnostic tumor and clinical response to nivolumab or reduced intensity CRT.

III. To describe the effects of reduced intensity CRT and nivolumab on viral HIV reservoirs.

IV. To identify the presence of cell-free plasma HPV deoxyribonucleic acid (DNA) before and after reduced intensity CRT and nivolumab and explore the relationship with clinical response.

V. To describe the effect of reduced intensity CRT on quality of life (QOL).

OUTLINE: Patients are assigned to 1 of 2 stratum.

HIGH-RISK STRATUM: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

LOW-RISK STRATUM: Patients receive mitomycin IV on day 1 and either fluorouracil IV on day 1 or capecitabine orally (PO) twice daily (BID) on Monday-Friday until the completion of radiation therapy at the discretion of the treating physician. Patients also undergo intensity modulated radiation therapy (IMRT) once daily (QD) for 20-23 treatment sessions over 6 weeks.

After completion of study treatment, patients are followed up at 6 weeks, every 3 months for years 1-2, every 6 months for year 3, and then annually for years 4-5.

Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer

Risk-Adapted Therapy for HIV-Associated Anal Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Will be presented using descriptive statistics (with no inferential statistics involved).

Relationship with clinical response with be explored. Will be presented using descriptive statistics (with no inferential statistics involved).

Evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval.

Evaluated by CTCAE version 5.0. The adverse events will be summarized by overall, as well as by grade using frequency (percentage). A two-sided 95% confidence interval will be reported together with percentage estimates. The proportion of participants who experience grade 3-4 toxicities will be estimated using a binomial point estimate and its 95% confidence interval.

Will be estimated using Kaplan-Meier method. The 95% confidence interval will be estimated using Greenwood's formula. The cumulative incidence of pelvic disease relapse will also be estimated from Kaplan-Meier method and the corresponding 90% confidence interval will be estimated using Greenwood's formula. In the analyses above, a two-sided p-value of 0.05 will be used to assess statistical significance.

Will be assessed by evaluating the changes from baseline in CD4+ using the Wilcoxon signed rank test to allow for nonnormality.

Will be assessed by evaluating the changes from baseline in HIV viral load using the Wilcoxon signed rank test to allow for nonnormality.

To assess cART adherence before, during, and after treatment with CRT and nivolumab to identify potential barriers to cART adherence when receiving concurrent oncological care.

Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity.

Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment

Questionnaire Administration

Alison K. Conlin

Nicholas DiBella

John A. Ellerton

Shahzad Siddique

Jay W. Carlson

James D. Murphy

Jason A. Zell

Tyler Robin

Gregory A. Masters

Anteneh A. Tesfaye

Lorraine Portelance

Michael D. Chuong

Patrick Kelly

Sudha R. Amarnath

John M. Schallenkamp

Daniel H. Barnett

Bryan A. Faller

Sheetal M. Kircher

Thomas Kim

Jennifer A Dorth

This phase II trial studies how well lower-dose chemotherapy plus radiation (chemoradiation) therapy works in comparison to standard-dose chemoradiation in treating patients with early-stage anal cancer. Drugs used in chemotherapy, such as mitomycin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more tumor cells. This study may help doctors find out if lower-dose chemoradiation is as effective and has fewer side effects than standard-dose chemoradiation, which is the usual approach for treatment of this cancer type.

PRIMARY OBJECTIVES:

I. To determine whether de-intensified chemoradiation for early stage squamous cell carcinoma of the anal canal (SCCA) is able to maintain excellent 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose chemoradiation therapy (CRT), as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year.

SECONDARY OBJECTIVES:

I. To compare changes in patient-reported outcomes (as per Fecal Incontinence Severity Index \[FISI\], Patient Reported Outcomes Measurement Information System \[PROMIS\], International Index of Erectile Function \[IIEF\], Sexual Function-Vaginal Changes Questionnaire \[SVQ\], and Vaginal Assessment Scale \[VAS\]/Vulvar Assessment Scale \[VuAS\] instruments) between the experimental and control arm.

II. To compare patterns of failure (local and regional relapse versus distant; in-field versus out-of-field of radiation), disease control, and overall survival between experimental and control arm.

III. To correlate vaginal dilator use during radiation delivery with sexual function.

IV. To measure changes in serum total testosterone from baseline to up to 12 months after radiation.

V. To validate the utility of image features of inguinal and pelvic lymph nodes obtained prior to treatment as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified chemoradiation is appropriate.

VI. To determine whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer.

VII. To determine the incidence of and predictors for cardiovascular toxicity in patients receiving fluorouracil (5-FU) or capecitabine.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A (STANDARD-DOSE CHEMORADIATION): Patients undergo 28 fractions of intensity-modulated radiation therapy (IMRT). Within 24 hours, patients also receive mitomycin intravenously (IV) over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 and 29-32 or capecitabine orally (PO) twice daily (BID) 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity.

ARM B (DE-INTENSIFIED CHEMORADIATION): Patients undergo 20 or 23 fractions of IMRT. Within 24 hours, patients also receive mitomycin IV over 30 minutes or less on day 1 and either fluorouracil IV over 24 hours on days 1-4 or capecitabine PO BID 5 days per week (Monday - Friday) until completion of IMRT in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks, every 3 months for years 1-2, every 6 months for year 3, then annually for years 4-5.

Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study

A Randomized Phase II Study De-Intensified ChemoRadiation for Early-Stage Anal Squamous Cell Carcinoma (DECREASE)

Will be compared between experimental and control arm. Will be estimated for all treatment arms using the Kaplan-Meier method (1958).

An event is local-regional failure, distant metastasis and chemoradiation-related death. Will determine if de-intensified chemoradiation achieves 2-year disease control of 85% or higher while improving anorectal health-related quality of life (HRQL), compared to standard-dose CRT, as measured by the change in the Fecal Incontinence Quality of Life scale (FIQoL) instrument coping/behavior domain from baseline to 1 year. The co-primary endpoints of disease control and FIQoL will be formally assessed in a hierarchical manner with disease control being assessed first. Will be estimated for all treatment arms using the Kaplan-Meier method (1958).

Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm.

Will compare changes as per HRQL: Health Related Quality of Life FACT-G (Functional Assessment of Cancer Therapy-General - Scoring: 0 - 32 with higher worse) between the experimental and control arm. Quality of life analyses, will be compared between arms using a two-sample independent t-tests at a significance level of 0.05 and appropriate longitudinal models will be evaluated to assess the trajectory of HRQL endpoints over time and to evaluate those trajectories between treatment arms. Overall score and change from baseline will be summarized using mean and standard deviation at each time point for each arm.

Will compare changes as per Fecal Incontinence Severity Index \[FISI - Scoring: 0 - 61 with lower better\] between the experimental and control arm.

Will compare changes as per International Index of Erectile Function \[IIEF\], Erectile Dysfunction: Scoring 7 - 35 with lower better. Ejaculation Frequency: Scoring 1 - 5 with lower better - between the experimental and control arm.

Will compare changes as per Orgasm ability/pleasure (PROMIS-Brief): scoring 2 - 10 with lower better - between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Anal Discomfort/pain (PROMIS- Full): scoring 3 - 15 with lower better. - between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Satisfaction with sex life (PROMIS-Brief) (scoring 2 - 10 with higher better) between the experimental and control arm.

PROMIS = Patient Reported Outcomes Measurement Information System

Will compare changes as per Therapeutic Aids for Sexual Function - Male (Scoring 6 - 22 with lower better) between the experimental and control arm.

Will compare changes as per Therapeutic Aids for Sexual Function - Female (Scoring 5 - 17 with lower better) between the experimental and control arm.

Will compare changes as per Sexual Function-Vaginal Changes Questionnaire \[SVQ\] (Scoring 5 - 26 with higher better) between the experimental and control arm.

Will compare changes as per Vaginal Assessment Scale \[VAS\]/Vulvar Assessment Scale \[VuAS\] (Scoring:0 - 22 with lower better) between the experimental and control arm.

Will be compared between experimental and control arm. The cumulative incidence method will be used to estimate local-regional and distant failure rates and the failure rates for the experimental treatment will be compared against the control using a failure specific log rank test.

Vaginal dilator use during radiation delivery will be correlated with sexual function.

Will be validated as a prognostic indicator that can identify patients with early-stage anal squamous cell carcinoma for whom treatment with de-intensified CRT is appropriate.

Will determine whether an online, interactive educational tool (eContour) may improve the quality of radiation target delineation for anal cancer.

Rates of grade 3+ adverse events (Common Terminology Criteria for Adverse Events \[CTCAE\], version \[v.\] 5) will be estimated using a binomial distribution along with their associated 95% confidence intervals and compared using Fisher's exact test between arms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab After Combined Modality Therapy in Treating Patients With High Risk Stage II-IIIB Anal Cancer	NCT03233711	Anal Basaloid S... Anal Canal Cloa... Anal Margin Squ... Stage IIB Anal ... Stage III Anal ...	Biopsy Biospecimen Col... Colonoscopy Computed Tomogr... Digital Rectal ... High Resolution... Magnetic Resona... Nivolumab Patient Observa... Proctoscopy Sigmoidoscopy X-Ray Imaging	18 Years -	National Cancer Institute (NCI)
Therapy Adapted for High Risk and Low Risk HIV-Associated Anal Cancer	NCT04929028	AIDS-Related An... Anal Basaloid S... Anal Canal Cloa... Anal Margin Squ... Anal Squamous C... HIV Infection Rectal Squamous... Stage I Anal Ca... Stage II Anal C... Stage II Rectal... Stage III Anal ... Stage III Recta...	Capecitabine Fluorouracil Intensity-Modul... Mitomycin Nivolumab	18 Years -	National Cancer Institute (NCI)
Lower-Dose Chemoradiation in Treating Patients With Early-Stage Anal Cancer, the DECREASE Study	NCT04166318	Anal Basaloid C... Anal Canal Cloa... Anal Canal Squa... Anal Margin Squ... Stage I Anal Ca... Stage IIA Anal ...	Capecitabine Fluorouracil Intensity-Modul... Mitomycin Quality-of-Life... Questionnaire A...	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for anal margin squamous cell carcinoma