Decitabine and Gemcitabine for Pancreatic Cancer and Sarcoma

Study Overview
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Brief Summary
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The purpose of this Phase 1b study is to assess the safety and maximum tolerated dose (MTD) of Decitabine in combination with Gemcitabine among previously treated patients diagnosed with advanced pancreatic adenocarcinoma or sarcoma (soft tissue and bone).

Detailed Description
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The objectives of this study are to assess the safety and tolerability of the combination of Decitabine with Gemcitabine in previously treated patients with advanced pancreatic cancer and advanced sarcoma and to define the recommended Phase II dose and describe the dose-limiting toxicity of the combination of Decitabine with Gemcitabine. The preliminary efficacy parameters of the combination of Decitabine with Gemcitabine will be estimated in terms of response rate, disease control rate and progression-free survival.

Official Title
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A Phase 1b Study: Treatment of Refractory Pancreatic Adenocarcinoma and Advanced Soft Tissue or Bone Sarcomas Using Decitabine Combined With Gemcitabine

Conditions
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Pancreatic Ductal Adenocarcinoma, Sarcoma

Intervention / Treatment
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* Drug: Decitabine
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have metastatic histologically or cytologically confirmed pancreatic adenocarcinoma or sarcoma (soft tissue or bone). Patient may enroll if he or she refuses first line therapy. Age ≥18 years. ECOG performance status ≤2 (Karnofsky ≥60% (See Appendix 1). Life expectancy of greater than 3 months (does not apply to pancreatic cancer population). Measureable disease per RECIST criteria. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count ≥1,500/mm3 Platelets ≥100 k/mm3 Total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal Creatinine </= 1.5 ULN Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) from time of consent and for the duration of study participation as well as for 3 months after the completion of study drug. Adequate contraception consists of a double method of contraception, one method of which must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). If a woman (or a male subject's female partner) becomes pregnant or suspects she is pregnant while she is participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Chemotherapy or radiotherapy within 4 weeks (for targeted therapies 5 half-lives) prior to entering the study or failure to recover from adverse events due to agents administered to </= grade 1 or stable grade 2, at the discretion of the treating physician. Patients who are receiving any other investigational agents. Known brain metastases. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Decitabine or other agents used in study. Prior Decitabine for the treatment of this cancer. Patients with previous exposure to therapy with Gemcitabine are allowed in the study. Pregnant or breast feeding women are excluded from participating in this study. WOCBP must have a negative serum pregnancy test within 7 days of the first administration of Decitabine. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

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: Decitabine and Gemcitabine<br>Decitabine, Dose escalation starting at 0.1mg/kg, subcutaneously administered on twice weekly schedule for three weeks of a 28 day cycle. Gemcitabine fixed infusion rate of 900 mg/m2, IV over 90 min, on Days, 1, 8 and 15 of a 28-day cycle. | Drug: Decitabine<br>* Dose escalation starting at 0.1mg/kg, subcutaneously administered on twice weekly schedule for three weeks of a 28 day cycle. Dose Escalation Schedule Dose Level/Dose of Decitabine per cycle Level -2: 0.1 mg/kg SQ twice weekly for 1 week; Level -1: 0.1 mg/kg SQ twice weekly for 2 weeks; Level 1*: 0.1 mg/kg SQ twice weekly for 3 weeks; Level 2: 0.2 mg/kg SQ twice weekly for 3 weeks; *Starting Dose Level<br>* Other names: Dacogen;Drug: Gemcitabine<br>* Fixed infusion rate of 900 mg/m2, IV over 90 min, on Days, 1, 8 and 15 of a 28-day cycle. Dose Escalation Schedule Dose Level/Dose of Decitabine per cycle Level -2: 0.1 mg/kg SQ twice weekly for 1 week; Level -1: 0.1 mg/kg SQ twice weekly for 2 weeks; Level 1*: 0.1 mg/kg SQ twice weekly for 3 weeks; Level 2: 0.2 mg/kg SQ twice weekly for 3 weeks; *Starting Dose Level<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity - To examine the toxicity related to the therapy by measuring the number of treatment related adverse events in patients | Non-Hematologic - Any grade 3,4 solid organ toxicity not explainable by another cause in the opinion of the principal investigator | All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s) up to 30 days after the last date of any study therapy | 
| Tumor Response Rate - Change at evaluations | Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. | Change on two consecutive evaluations at least 8 weeks apart up to 30 days after the last date of any study therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) | DCR is defined as the proportion of patients who achieved a complete response (CR), partial response (PR) or stable disease (SD). | Patients will be evaluated weekly during each cycle of treatment up to 30 days after the last date of any study therapy | 
| Progression-free survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death due to any cause, whichever occurs first. | Patients will be evaluated weekly during each cycle of treatment up to 30 days after the last date of any study therapy | 
| Overall survival (OS) | OS is defined as the duration of time from start of treatment to death due to any cause. | Patients will be evaluated weekly during each cycle of treatment up to 30 days after the last date of any study therapy |