Maintenance Metronomic Chemotherapy for Metastatic Colorectal Carcinoma

Metronomic Chemotherapy With Anti-angiogenic Effect as Maintenance Treatment for Metastatic Colorectal Carcinoma Following Response to FOLFIRI+Bevacizumab: Clinical and Laboratory Studies

Colorectal cancer patients with metastases (mCRC) at response under expensive chemotherapy which may be toxic +/- exhausting are candidates for an effective and more convenient maintenance treatment.

Objectives:

1. To define the efficacy of maintenance chemotherapy by a low-dose metronomic (LDM) regimen, in metastatic CRC patients responding under FOLFIRI + bevacizumab.
2. To discover predictive factors for response to this LDM regimen.

Hypothesis:

1. The re-growth of residual metastases can be slowed by the anti-angiogenic effects of LDM chemotherapy.
2. Serial measurements of angiogenic/ inflammatory factors in the plasma and/or evaluation of certain enzymes in the tumor may discover predictive factors of response to LDM chemotherapy in metastatic CRC patients.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Drug: CAPECITABINE, CELECOXIB and METHOTREXATE

Detailed Description

At entry to the research protocol the up-till then administered treatment with Intra Venous FOLFIRI+BEVACIZUMAB will be stopped.Instead, the research oral treatment will be initiated to be taken daily on an ambulatory basis and under once monthly re-evaluation. If and when disease progresses the original FOLFIRI+BEVACIZUMAB treatment will be considered for re-institution.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Afula, Israel, 18101
    • HaEmek Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologic (or cytologic) proof of colorectal carcinoma (CRC).
2. Age: between 18 and 80.
3. Sex: both sexes.
4. Previous treatment for metastatic disease is limited to FOLFIRI+ bevacizumab.
5. Prior adjuvant chemotherapy, with a fluoropyrimidine and/or Oxaliplatin, is allowed.
6. Prior radiotherapy, either as adjuvant treatment or palliation of metastatic sites is allowed, provided that there are other non-irradiated foci of disease for evaluation.
7. Persistent remission, either complete, partial or minimal response (CR, PR or MR) or stable disease (SD), one year+/-one month from initiation of first line treatment for mCRC.
8. Asymptomatic patients at break from chemotherapy.
9. Intact organ function, including complete blood counts (CBC) showing normal values or any toxicity limited to grade 1 and blood chemistry (SMA) showing liver and renal functions < 1.5 upper normal limit (UNL).
10. Capability to understand and to sign the informed consent.

Exclusion Criteria:

1. Concurrent any other cancer (except BCC or squamous cell carcinoma of skin).
2. Inability to adhere to monthly visits to the oncology unit for evaluation.
3. Presence of brain metastases.
4. Any current or recent (within the last month) continuous treatment by steroids or by NSAIDs, or with therapeutic doses of anticoagulants for any reason.
5. Previous radiotherapy to the only site of measurable disease.
6. Evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac including arrhythmias, hepatic or renal disease), and/or existence of active peptic ulcer (clinically and/or by gastroscopy).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LDM anti-angiogenic chemotherapy; LDM (Low Dose Metronomic) anti-angiogenic chemotherapy includes daily oral treatment with CAPECITABINE, CELECOXIB and METHOTREXATE.	Drug: CAPECITABINE, CELECOXIB and METHOTREXATE; daily oral treatment with CAPECITABINE, CELECOXIB and METHOTREXATE; Other Names: Metronomic Chemotherapy
No Intervention: observation; observation only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of progression free survival (PFS), measured in months.	From start of the experimental treatment until the date of first documented progression or date of death of any cause,whichever came first, assessed up to 12 months.	Up to 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity profile of treatment, defined by CTCAE Version 4.0.	From start of the experimental treatment until the date of first documented progression or date of death of any cause,whichever came first, assessed up to 12 months.	up to12 months
Changes in levels of angiogenic factors while under treatment: VEGF, PDGF, TSP-1	Change from baseline in levels of angiogenic factors at 4 months of treatment.	Up to 4 months.
Quality of life, as expressed by FACT-C.	Change from baseline in parameters of Quality of life until the end of treatment, assessed up to 12 months.	Up to 12 months.

Collaborators and Investigators

• Sponsor: HaEmek Medical Center, Israel
• Collaborators: Clalit Health Services
• Investigators: Principal Investigator: David Loven, MD, Ha'Emek MC

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: March 11, 2012
• First Submitted That Met QC Criteria: August 16, 2012
• First Posted (Estimate): August 20, 2012

Study Record Updates

• Last Update Posted (Estimate): July 8, 2015
• Last Update Submitted That Met QC Criteria: July 6, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Colorectal Cancer Metastatic; Maintenance Treatment; Metronomic Chemotherapy; Anti-Angiogenic
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Cyclooxygenase 2 Inhibitors; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Capecitabine; Celecoxib; Methotrexate
• Other Study ID Numbers: EMC-0047-11