Midostaurin (PKC412) for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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This study combines midostaurin (PKC412) with radiation and a standard chemotherapy drug call 5-Fluorouracil (5-FU) for subjects with advanced rectal cancer. Midostaurin is a type of kinase inhibitor which works by blocking proteins associated with cancer cell growth. Previous studies also suggest that midostaurin may help increase the effectiveness of radiation therapy. In this research we are looking for the highest dose of midostaurin that can be given safely in combination with standard chemoradiation.

Detailed Description
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Midostaurin capsules will be taken by mouth for 8 weeks. For the first 2 weeks midostaurin will be taken alone (no chemoradiation). After 2 weeks standard chemoradiation will be added to the midostaurin regimen. Subjects receive midostaurin and chemoradiation for an additional 6 weeks. Physical exams will be done weekly. Blood samples will be taken and an optional tumor biopsy will be performed in week 2. 4-5 weeks after completing chemoradiation and midostaurin subjects will undergo surgery as standard of care. Tumor tissue from the surgery will be used for research purposes. A Ct scan of chest, abdomen, and pelvis will be performed. After completion of surgery, subjects will have an end of study visit with physical exam, blood tests. CT scans of chest, abdomen, and pelvis will be performed yearly for 5 years.

Official Title
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Phase I Study of Chemoradiation With Midostaurin (PKC412) For Locally Advanced Rectal Cancer

Conditions
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Adenocarcinoma of the Rectum

Intervention / Treatment
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* Drug: Midostaurin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of the rectum T3/4 or N+ disease Life expectancy > 3 months Normal organ and marrow function Exclusion Criteria: Metastatic disease Pregnant or breastfeeding Prior radiotherapy Receiving other investigational agents History of inflammatory bowel disease Active scleroderma or CREST syndrome Uncontrolled intercurrent illness History of a different malignancy unless disease free for at least 5 years HIV or active viral hepatitis Impaired cardiac function

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midostaurin with chemoradiation<br> | Drug: Midostaurin<br>* 50 mg BID for 8 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine Maximum Tolerated Dose (MTD) of midostaurin in combination with standard 5-FU chemoradiation |  | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the rate of Dworak Tumor Regression Grade 3/4 for locally advanced rectal cancer treated with study combination at the MTD, stratified by KRAS status (mutant vs. wild type) |  | 1.5 years | 
| To determine surgical complication rate in patients who received preoperative radiation therapy |  | 1.5 years | 
| Perform an exploratory analysis of the impact of selected mutations in APC, PTEN, BRAF, NRAS, and PIK3CA, among other genes |  | 1.5 year | 
| To evaluate proteomic markers of response and resistance to midostaurin-based chemoradiation |  | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, chemotherapy, chemoradiation