Neoplasms

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Adenocarcinoma

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Oxaliplatin

Capecitabine

Azacitidine

Decitabine

Antimetabolites

Enzyme Inhibitors

Dose Escalation of Azacitidine + CAPOX (Capecitabine, Oxaliplatin)

Starting dose level 75 mg/m2/day subcutaneously on Days 1-5 of a 21 day cycle.

1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14 of a 21 day cycle.

Starting dose level 90 mg/m2 by vein on Day 2 of a 21 day cycle.

Highest tolerable dose of combination azacitidine with CAPOX found in Phase I.

Azacitidine MTD

Michael Overman, MD

The goal of the Phase I portion of this study is to find the highest tolerable dose of azacitidine combined with capecitabine and oxaliplatin (CAPOX) that can be given to patients with metastatic colorectal cancer.

The goal of the Phase II portion of this study is to learn if azacitidine, given in combination with CAPOX, can help to control metastatic colorectal cancer. The safety of this drug combination will also be studied.

The Study Drugs:

Azacitidine is designed to block certain proteins in cancer cells whose job is to stop the function of the tumor-fighting proteins. By blocking the "bad" proteins, the tumor-fighting genes may be able to work better.

Capecitabine is designed to interfere with the growth of cancer cells.

Oxaliplatin is designed to keep new cancer cells from growing.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. Up to 4 groups of up to 3-6 participants will be enrolled in the Phase I portion of the study, and up to 30 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of azacitidine and oxaliplatin you receive will depend on when you joined this study. All participants will receive the same dose of capecitabine. The first group of participants will receive a low dose level of the combination. Each new group will receive a higher dose of the combination than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the combination of azacitidine, oxaliplatin, and capecitabine is found.

If you are enrolled in the Phase II portion, you will receive the combination of azacitidine, oxaliplatin, and capecitabine at the highest dose that was tolerated in the Phase I portion.

Central Venous Catheter (CVC):

Before you can begin to receive oxaliplatin on this study, you will have a CVC placed if you do not have one already. A CVC is a sterile, flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Study Drug Administration:

A cycle of treatment is defined as 21 days.

Azacitidine will be injected under your skin on Days 1-5 of each cycle.

You will receive oxaliplatin by vein over 2 hours on Day 2 of each cycle.

You will take capecitabine by mouth 2 times each day on Days 1-14 of each cycle. Capecitabine tablets should be taken 12 hours apart, within 30 minutes after eating a meal.

Study Visits:

Up to 3 days before or on Day 1 of each cycle, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will have a neurosensory assessment.
* Your performance status will be recorded.
* You will be asked about any symptoms and/or side effects you may be experiencing and any drugs you may be taking.
* Blood (about 2 tablespoons) will be drawn for routine tests.

On Day 5 of Cycle 1 and Days 1 and 5 of Cycle 2, before you receive any of the study drugs, blood (about 2 teaspoons each time) will be drawn to test for CIMP, a chemical "marker" in the blood that may be related to how the drug may affect the cancer.

After every 3 cycles (Cycles 4, 7, 10 and so on), you will have a CT or MRI scan of the chest, abdomen, and/or pelvis to check the status of the disease.

Length of Study:

You may continue to take the study drugs for as long as you are benefitting. You will be taken off the study drugs if the disease gets worse, you experience any intolerable side effects, or if the study doctor thinks it is in your best interest to stop taking the study drugs.

If you chose to stop your participation in this study at any time, you should tell the study doctor or study staff right away. They will make sure that proper procedures are followed and a final visit is made for your safety.

End-of-Treatment Visit:

Within 10 days after your study treatment ends for any reason, you will return to the clinic and the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your weight and vital signs.
* You will have a neurosensory assessment.
* Your performance status will be recorded.
* You will have a CT scan or MRI scan of the chest, abdomen, and/or pelvis to check the status of the disease.
* You will be asked about any symptoms and/or side effects you may be experiencing and any drugs you may be taking.
* Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up:

The study doctor and study staff will follow your health status for the first 30 days after you stop taking the study drugs to check if you are experiencing any treatment-related side effects. The follow-up will be done during your regularly scheduled routine clinic visits and/or by phone call, which should last about 5 minutes.

If you continue to experience any treatment-related side effects after the 30 days of follow-up, the study staff will continue to follow up with you during your regularly scheduled clinic visits until the side effects have gotten better or become stable.

Long-Term Follow-Up:

Every 3 months after the end-of-treatment visit, the study staff will contact you by phone or email to check on how you are doing. If you are contacted by phone, the call should last about 5 minutes. Your medical records may also be reviewed.

This is an investigational study. Azacitidine is FDA approved and commercially available for myelodysplastic syndrome (MDS - a blood disease that often leads to cancer). Its use in colorectal cancer is investigational.

Oxaliplatin and capecitabine are both FDA approved and commercially available as treatment for colorectal cancer.

The use of azacitidine, oxaliplatin, and capecitabine in combination is investigational.

Up to 54 patients will take part in this study. All will be enrolled at MD Anderson.

Azacitidine and CAPOX in Metastatic Colorectal Cancer

Phase I/II Study of Azacitidine and CAPOX (Capecitabine + Oxaliplatin) in Metastatic Colorectal Cancer Patients Enriched for Hypermethylation of CpG Promoter Islands

Dose just below the one at which ≥ 1/3 of subjects experience a dose limiting toxicity (DLT) considered the MTD.

Per Response Evaluation Criteria in solid Tumors Criteria (RECISTv1.0) for target lesions and assessed by CT or MRI: Partial Response (PR), \>= 30%decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither PD nor PR, the sum of the longest diameters no change or increase by \<20% from baseline or from nadir (smallest sum on treatment); Progressive Disease (PD), the sum of the longest diameters increases by\>= 20% from nadir (smallest sum on treatment). For non-target lesions assessed by CT or MRI: Stable Disease (SD), Persistence of \>=1 non-target lesion; Progressive Disease (PD), Enlargement of non-target lesions and/or appearance of new lesions.

Celgene

M.D. Anderson Cancer Center

Dose Escalation of Azacitidine + CAPOX (Capecitabine, Oxaliplatin)

Of 21 day cycle, starting dose Azacitidine 75 mg/m2/day subcutaneously on Days 1-5; Capecitabine 1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14; and Oxaliplatin starting dose 90 mg/m2 by vein on Day 2.

Phase I: Starting Dose

Subcutaneous Azacitidine 75 mg/m2/day days 1 to 5, intravenous Oxaliplatin 110 mg/m2 day 2, and oral capecitabine 1500 mg/m2 divided twice daily for 2 weeks every three weeks

Phase I: Highest Dose Level

MTD of Azacitidine + CAPOX

Of a 21 day cycle, Azacitidine MTD (Highest tolerable dose of combination azacitidine with CAPOX found in Phase I); Capecitabine 1500 mg/m2/day by mouth twice daily in divided doses on Days 1-14; and Oxaliplatin starting dose 90 mg/m2 by vein on Day 2.

Phase II

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Michael J Overman/ Professor, GI Medical Oncology

Azacitidine+CAPOX (Capecitabine, Oxaliplatin)

Maximum Tolerated Dose (MTD) of Azacitidine, and Capecitabine and Oxaliplatin (CAPOX)

NA (Early Progression)

PD (Progression Disease)

SD (Stable Disease)

Response Rate of Azacitidine, and Capecitabine and Oxaliplatin (CAPOX)

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinogenesis

Cell Transformation, Neoplastic

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Micronutrients

Hematinics

Vitamins

Vinorelbine

Paclitaxel

Carboplatin

Pemetrexed

Docetaxel

Albumin-Bound Paclitaxel

Cisplatin

Tubulin Modulators

Antimitotic Agents

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Patient will receive 5-azacitidine at a dose of 75 mg/m2 intravenously daily on day 1-5 every 28 days for 6 cycles

Vidaza

Obtained from tissue of resected NSCLC tumor.

Tumor Specimen for Methylation Analysis

Pre-Surgery, Post-Surgery, Post-Vidaza Therapy and during follow-up.

Blood Sample for Methylation Analysis

Ikechukwu Akunyili, MD

The trial investigates the feasibility and efficacy of targeting Non-Small Cell Lung Cancer (NSCLC) "driven" by epigenetic changes. The investigators study the impact of 5-azacitidine (Vidaza®, Celgene, Summit, NJ, USA) in combination with conventional cytotoxic chemotherapy in a sequential fashion. The study population consists of all NSCLC patients who undergo "curative" lung cancer resection and whose tumors harbor hypermethylation in any of the protocol-specific genes (samples will be banked for additional molecular testing including other 21 loci which have shown to be important in lung carcinogenesis.

Adjuvant chemotherapy has become an essential part for the treatment of stage IB-IIIA NSCLC patients based on 4 randomized clinical trials showing survival advantage for patients who received adjuvant CT, oncologists initially started to adapt this modality of treatment for pathologically stage IB-IIIA NSCLC patients \[4\]. Herein, NSCLC patients will be treated in the adjuvant setting with conventional doublet platinum-based chemotherapy followed by 5-azacitidine, a demethylating agent. The planned dosages to be used in this trial have been extensively studied in previously conducted clinical trials involving all therapeutic agents.

All patients will undergo thorough surgical resection of the primary lung tumor, and evidence of promoter hypermethylation of gene(s) must be present in the tumor specimen and/or blood sample (plasma or WBC). The collection of tumor specimen will be considered a priority to correlate the tumor "methylation pattern/profile" with the serum "methylation pattern/profile". If tumor specimen is not available for any reason, but the patient has at least one of the 9 targeted genes hypermethylated in the serum, the patient is eligible to be enrolled into the trial.

Treatment will consist of 2 parts:

Part A. Adjuvant chemotherapy.

Following surgical resection of NSCLC and test positive for promoter hypermethylation in at least one (1) of the targeted TSGs described, patient will start adjuvant conventional chemotherapy (doublet platinum-based chemotherapy) for stage IB-IIIA NSCLC. In the case a patient with stage IB refuses adjuvant chemotherapy, the patient still can be enrolled into Part B of the study if he/she understands the concept of the trial and sign an informed consent.

Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC. Those patients will be treated with pemetrexed. Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Pegfilgrastim, a granulocyte-colony stimulating factor (G-CSF), will be allowed on day 2 at discretion of the clinician.

All patients should be premedicated prior to paclitaxel or docetaxel administration in order to prevent severe hypersensitivity reactions (HSR). Such premedication may consist of: dexamethasone 20 mg orally administered approximately 12 and 6 hours before paclitaxel or docetaxel; diphenhydramine 50 mg intravenously and cimetidine (300 mg) or ranitidine (50 mg) intravenously 30 minutes before paclitaxel. In case of pemetrexed, patient will received an injection of vitamin B-12 1,000 mcg IM a week prior to start therapy as well as folic acid 1 mg po daily a week before pemetrexed infusion and during the entire course of treatment with this antifolate agent.

The dosages and toxicities of these chemotherapy agents are very well described in the clinical setting, and patients will be managed as any other patient receiving standard chemotherapy.

Part B. Targeted therapy using 5-azacitidine.

If the patient decides not to receive adjuvant chemotherapy, the patient still can be enrolled into the study, if the patient understands the concept of chemoprevention and consents to blood sampling during 5-azacitidine administration and follow-up (informed consent signed). This part of the study consists of 6 cycles of 5-azacitidine (Vidaza®, Celgene, Summit, NJ, USA).

Four weeks after completion of adjuvant chemotherapy (day 28 from day 1 of last cycle of chemotherapy), the patient will continue his/her treatment plan with 6 cycles of 5-azacitidine. To be eligible for this part of the study, patient must have no evidence of disease (NED). Thus, patient will be assessed by CT scan chest/abdomen/pelvis with and without intravenous contrast prior to initiating Part B. In case of iodine allergy/anaphylaxis history, patient will be assessed with MRI. Progression of disease will be defined by RECIST criteria.

Patient will receive 5-azacitidine at a dose of 75 mg/m2 intravenously daily on day 1-5 every 28 days for 6 cycles. Biological correlatives will be performed during this period. Toxicity management is described in section 6.0. The use of growth factor support (either erythropoietin stimulating agents or G-CSF) will be also allowed at discretion of the treating physician.

Anatomical Studies:

All patients will have surgical resection of the primary tumor. Pieces of the resected tumor and non-tumor lung tissues that are not required for pathological evaluation will be frozen in optimum temperature compound (OTC) and saved for molecular analysis.

As part of the enrollment process, patient will be assessed through CT scan of the chest/abdomen/pelvis with and without intravenous contrast or with MRI in case of contraindication for iodine contrast, prior to initiate Part B of the treatment (confirming clinically and radiological "no evidence of disease-NED"). Another assessment will be performed 4 weeks after the last dose of 5-azacitidine (to confirm NED status). Patient will be clinically followed up every 3 months until completion of 2 years post-treatment. Imaging tests will be performed every 3 months with CT scan as part of the standard follow-up until completion of 2 years post-surgery. After 2 years of post-treatment completion, patient will be followed up every 6 months in the clinic and also by radiographic studies until completion of 5 years post-treatment. In the case of clinical suspicion for progression, patient will undergo a thorough and complete work-up to rule out this possibility. This may include imaging diagnostic tests, biopsy, or other tests and procedures.

Biological Correlatives:

The premise of the study is that certain loci will be hypermethylated in the lung cancer specimen of the patients. For some loci (which we shall call Type I) the tumor will show significantly elevated methylation compared to adjacent histologically normal tissue, thus providing a cancer-specific methylation signal. Other loci (which we will refer to as Type II) may be methylated in the tumor as well as in the adjacent "histologically" normal tissue and/or WBCs. These loci will not be cancer-specific markers, though they may indicate precancerous changes or they may be indicative of "cancer risk". Their hypermethylation may be age-associated or environmentally induced, yielding "field effects" or "field defects". Field defects would consist of molecular alterations (in this case hypermethylation) that are not yet visible as histological changes.

Independent of whether a hypermethylated locus is specific for overt cancer (Type I) or not (Type II), it would be of interest for the study. These Type II changes would be "hypothesis generating". Since it has been well documented in the literature that DNA from cells can be shed into the blood stream (more so in the case of cancer patients), it would be expected that at least for some of the loci that are hypermethylated (Type I and II), this methylation would be detectable in the plasma. Tumor tissue methylation will be correlated with serum obtained at the time of tumor resection.

It might be expected that complete resection would lead to a reduction or complete disappearance in the methylation signal for Type I loci in the plasma, since the source of the signal has been removed. Type II also shows methylation in the tissue adjacent to the tumor, these loci might continue to provide signal in the plasma (though it may be somewhat diminished).

Type I loci would therefore be of great use to verify complete resection and to monitor recurrence (one would anticipate the signal to increase again as the cancer grows back), while Type II loci would be a great tool to monitor the efficacy of demethylating drugs. It must be acknowledged that the spectrum of Type I and Type II methylation may not be sharply delineated.

Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer (NSCLC) As Part of Adjuvant Therapy and Preventive Strategy

Pilot Study Targeting Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer As Part of Adjuvant Therapy and Preventive Strategy

To determine the feasibility and efficacy of incorporating a demethylating agent (5-azacitidine; Vidaza®, Celgene, Summit, NJ, USA) as part of adjuvant therapy in patients diagnosed with NSCLC who harbor methylated tumor supressor genes (TSGs) in their tumor tissue and/or serum. Response to be evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.0.

To measure the grade of demethylation induced by 5-azaciditine on specific TSGs by analyzing plasma DNA, and global demethylation by analyzing WBC DNA, and determine the duration of this effect.

University of Miami

Assistant Professor of Clinical

Cisplatin: Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Carboplatin: Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Paclitaxel: Patients will receive a total of 4 cycles of adjuvant chemotherapy (each cycle given every 21 days). Conventional chemotherapy will be selected at discretion of the treating physicians except on those cases in which pathologic diagnosis indicates non squamous NSCLC.

Vidaza: Patient will receive 5-azacitidine at a dose of 75 mg/m2 intravenously daily on day 1-5 every 28 days for 6 cycles

Adjuvant Chemotherapy + Vidaza

Study data were not analyzed due to insufficient number of evaluable patients.

Ikechukwu Akunyili MD

Percentage of Patients Showing a Presence of Methylated Tumor Suppressor Genes in Their Tumor Tissue and/or Serum Achieving Partial or Complete Response to Protocol Therapy.

Degree of Demethylation in Patient Tumor Tissue and/or Serum Induced by 5-azacitidine on Specific Tumor Specific Genes (TSGs)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Azacitidine and CAPOX in Metastatic Colorectal Cancer	NCT01193517	Colorectal Canc...	Azacitidine Capecitabine Oxaliplatin Azacitidine MTD	18 Years -	M.D. Anderson Cancer Center
Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer (NSCLC) As Part of Adjuvant Therapy and Preventive Strategy	NCT01209520	Lung Cancer Non Small Cell ... Hypermethylatio...	Cisplatin Carboplatin Paclitaxel Vidaza Tumor Specimen ... Blood Sample fo... Vinorelbine Docetaxel Pemetrexed	18 Years -	University of Miami
Residual Hypermethylation in Early Stage Non-Small Cell Lung Cancer (NSCLC) As Part of Adjuvant Therapy and Preventive Strategy	NCT01209520	Lung Cancer Non Small Cell ... Hypermethylatio...	Cisplatin Carboplatin Paclitaxel Vidaza Tumor Specimen ... Blood Sample fo... Vinorelbine Docetaxel Pemetrexed	18 Years -	University of Miami

Spots Global Cancer Trial Database for hypermethylation