Cisplatin and Fluorouracil Compared With Carboplatin and Paclitaxel in Treating Patients With Inoperable Locally Recurrent or Metastatic Anal Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well cisplatin and fluorouracil work compared with carboplatin and paclitaxel in treating patients with anal cancer that cannot be removed by surgery, has come back at or near the same place as the primary tumor, or spread to other places in the body. Drugs used in chemotherapy, such as cisplatin, fluorouracil, carboplatin and paclitaxel, 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. It is not yet known whether cisplatin and fluorouracil are more effective than carboplatin and paclitaxel in treating anal cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate best overall response rate (ORR). SECONDARY OBJECTIVES: I. Overall survival (OS). II. Progression free survival (PFS). III. Disease control rate (DCR) (stable disease [SD] or better) at 12 and 24 weeks. IV. Best ORR of non-irradiated lesions. V. Anti-tumor activity and magnitude of response as captured by waterfall plot analyses. VI. Toxicity. VII. Quality of life (QOL). VIII. Feasibility of conducting a multicenter international study on squamous cell carcinoma of the anus (SCCA) and recruit within a reasonable time frame. TERTIARY OBJECTIVES: I. Explorative biomarker analysis. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive cisplatin intravenously (IV) over 1-4 hours on day 1 and fluorouracil IV continuously over 24 hours on days 1-4. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with complications associated with the central venous access which prevent further infusion of fluorouracil and only after discussion with the Chief Investigator may receive capecitabine twice daily (BID) on days 1-4. ARM B: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Official Title
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InterAACT - An International Multicentre Open Label Randomised Phase II Advanced Anal Cancer Trial Comparing Cisplatin Plus 5-Fluorouracil Versus Carboplatin Plus Weekly Paclitaxel in Patients With Inoperable Locally Recurrent or Metastatic Disease

Conditions
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Anal Basaloid Carcinoma, Anal Canal Cloacogenic Carcinoma, Anal Squamous Cell Carcinoma, Metastatic Anal Canal Carcinoma, Recurrent Anal Canal Carcinoma, Stage IIIB Anal Canal Cancer, Stage IV Anal Canal Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Fluorouracil
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inoperable, locally recurrent or metastatic disease (tumor resectability should be assessed by a local surgeon or multidisciplinary team) Histological or cytological confirmation of epidermoid anal carcinoma (includes squamous, basaloid and cloacogenic lesions) from the primary tumor or a newly diagnosed recurrent/metastatic lesion Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 Previous definitive chemo-radiation is permitted for early stage tumors (cisplatin-based chemotherapy [chemo]-radiation is permitted but only if tumor progression/relapse occurs after 6 months from treatment completion) Previous systemic chemotherapy is permitted if administered as induction treatment (=< 2 cycles) before definitive chemoradiotherapy for early stage disease and there is no evidence of tumor progression during or after treatment completion Human immunodeficiency virus positive (HIV+) patients will be considered eligible if they are on highly active anti-retroviral therapy (HAART) and have a cluster of differentiation (CD)4 count of >= 200/ul (HIV+ patients who are on HAART and have a CD4 count < 200/ul are eligible if the plasma viral load is below the level of detection according to the local assay) Absolute neutrophil count (ANC) >= 1.5 x 10^9/l Platelets >= 100 x 10^9/l Hemoglobin (Hb) >= 9 g/dl for males and >= 8 g/dl for females Creatinine clearance >= 50 ml/minute Serum bilirubin =< 1.5 x upper limit of normal (ULN) Alanine transaminase (ALT) or aspartate transaminase (AST) =< 3 x ULN (if liver metastases are present, serum transaminases =< 5 x ULN are permitted) Fertile men and women must agree to take adequate contraceptive precautions during, and for at least six months after therapy Life expectancy of at least 3 months Exclusion Criteria: Tumors of adenocarcinoma, melanoma, small cell and basal cell histology are excluded Locally recurrent tumor which is amenable to curative resection (as deemed by a local surgeon or multidisciplinary team) Tumor relapse/progression within 6 months of completion of a cisplatin-based chemoradiotherapy regimen for the treatment of early stage tumors Previous administration of > 2 cycles of systemic chemotherapy as induction treatment before definitive chemoradiotherapy for early stage disease Tumor progression during or immediately after completion of =< 2 cycles of systemic chemotherapy as induction treatment before definitive chemoradiotherapy for early stage disease Previous use of systemic chemotherapy or other investigational drugs for the treatment of inoperable locally recurrent or metastatic tumors (previous use of radiotherapy in this setting is not an exclusion criterion if: 1) non-irradiated target tumor lesions are present at randomization for the purpose of tumor response assessment or 2) in the absence of non-irradiated target tumor lesions, progression of the irradiated tumor lesions according to the RECIST criteria version 1.1 is documented) Current or recent (within 30 days of first study dosing) treatment with another investigational drug or participation in another investigational study Documented or symptomatic brain metastases and/or central nervous system metastases or leptomeningeal disease Major surgery performed < 28 days from treatment start Palliative radiotherapy completed =< 7 days from treatment start Clinically significant (i.e. active) cardiac disease (e.g. symptomatic coronary artery disease, uncontrolled cardiac arrhythmia, or myocardial infarction within the last 6 months); any history of clinically significant cardiac failure History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan HIV+ patients who are not on HAART or have a CD4 count of < 200/ul in the presence of detectable plasma viral load according to the local assay Known history of active hepatitis B or hepatitis C infection Serious active infection requiring intravenous (i.v.) antibiotics at enrollment Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer Other clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this trial Known hypersensitivity to any of the study drugs or excipients Known peripheral neuropathy > grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible) Pre-existing hearing impairment Patients planning for a live vaccine Pregnant or lactating females

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (cisplatin, fluorouracil or capecitabine)<br>Patients receive cisplatin IV over 1-4 hours on day 1 and fluorouracil IV continuously over 24 hours on days 1-4. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with complications associated with the central venous access which prevent further infusion of fluorouracil and only after discussion with the Chief Investigator receive capecitabine BID on days 1-4. | Drug: Capecitabine<br> <br> * Other names: Xeloda;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm B (paclitaxel, carboplatin)<br>Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best ORR defined as the percentage of patients achieving confirmed partial (PR) or complete responses (CR) as per RECIST v1.1 | The ORR will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity and magnitude of response | Anti-tumor activity and magnitude of response will be captured by waterfall plot analyses. The percentage change in tumor size from baseline to the time of best response will be plotted by patients (ordered from worst to best) and bars colored according to best response. | Up to 3 years | 
| Best ORR of non-irradiated lesions defined as the percentage of patients achieving confirmed PR or CR as per RECIST v1.1 of non-irradiated sites of disease | The ORR of non-irradiated lesions will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test. | Up to 3 years | 
| Changes in QOL | QOL will be evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life and EuroQOL-5 dimension-5 level questionnaires. Differences from baseline will be compared between arms of the study using the two sample t-test or Wilcoxon non-parametric method as appropriate. | Baseline to up to 3 years | 
| DCR defined as CR, PR, or SD assessed according to RECIST criteria v1.1 | DCR will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test. | At 24 weeks post treatment start | 
| DCR defined as CR, PR, or stable disease (SD) assessed according to RECIST criteria v1.1 | DCR will be summarized as the percentage (including 95% confidence intervals) of responders and presented by treatment group and will be compared (as exploratory endpoint) between treatment groups using a chi-squared test. | At 12 weeks post treatment start | 
| Feasibility in terms of proportion of centers that successfully recruit at least one patient | The proportion of centers engaging will be presented with 95% confidence intervals. | Up to 36 months | 
| Feasibility in terms of recruitment rate | The recruitment rate will be calculated overall centers and by country and center. | Up to 36 months | 
| OS | The Kaplan Meier estimates of OS over time and median OS with associated 95% confidence intervals will be presented by treatment and (as exploratory endpoint) compared using a log rank test. Cox multivariate regression analysis will be used (as exploratory analysis) to calculate the hazard ratio between treatments along with its 95% confidence interval. The treatment effect will be adjusted for the stratification factors and other identified prognostic factors (e.g. time to disease relapse & whether pre-treated with platinum) in a multivariate setting. | From the date of randomization to the date of death from any cause, assessed up to 12 months | 
| PFS | The Kaplan Meier estimates of PFS over time and median PFS with associated 95% confidence intervals will be presented by treatment and (as exploratory endpoint) compared using a log rank test. Cox multivariate regression analysis will be used (as exploratory analysis) to calculate the hazard ratio between treatments along with its 95% confidence interval. The treatment effect will be adjusted for the stratification factors and other identified prognostic factors (e.g. time to disease relapse & whether pre-treated with platinum) in a multivariate setting. | From the date of randomization to the date of confirmed clinical/radiological progression or death from any cause, assessed up to 12 months | 
| Proportion of patients experiencing grade 3-5 toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | The proportion of patients experiencing grade 3-5 toxicity will be compared on a regimen basis using the chi-squared test. Fisher's exact test will be used when expected cell frequencies are < 5. | Up to 3 years | 
| Sensitivity analysis of ORR |  | Up to 3 years |