Low Dose Metronomic Poly-chemotherapy for Metastatic CRC

Phase 2

Completed

• Conditions: Colorectal Cancer
• Interventions: Drug: Capecitabine; Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Celecoxib

• Registration Number: NCT02280694
• Lead Sponsor: HaEmek Medical Center, Israel

Brief Summary

This study investigates the activity of a new regimen of treatment for patients with metastatic colorectal carcinoma. This includes a combination of well-known chemotherapy agents and anti-inflammatory agents, when administered orally at low daily doses and without planed brakes (Low Dose Metronomic regimen), in contrast with the conventional and already exhausted regimens of treatment at Maximal Tolerated Doses (MTD) which required pre-planned brakes between treatment days.

Detailed Description

Patients suffering from metastases of colorectal cancer whose tumor cells develop resistance to conventionally administered treatments are in need for new methods of treatment.

While their chemotherapy had been administered up till then at the classical regimen of Maximal Tolerated Doses (MTD), which is aimed to directly killing maximal fractions of tumor cells, the present study evaluates the clinical benefit of a treatment which is based on old chemotherapeutic and old anti-inflammatory drugs, when these are administered at low doses,on daily basis and orally taken, without planed brakes (Low Dose Metronomic regimen).

Treatments based on this type of regimen have already been studied on other models of cancer and showed the capacity of suppressing tumor growth by a new category of anti-tumor effects. Namely, by affecting factors and mechanisms which prevail in the microenvironment that surrounds tumor deposits, thus circumventing the resistance of their cancer cells to chemotherapy.

Study Timeline

• Study First Submitted: 2014-10-29
• Study First Submitted QC: 2014-10-30
• Study First Posted: 2014-10-31
• Study Start: 2015-01
• Primary Completion: 2019-01
• Study Completion: 2019-12
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-11
• Last Update Posted: 2020-02-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 45

Inclusion Criteria

1. Histological (or cytological) proof of colorectal carcinoma (CRC)

2. Measurable metastases

3. ECOG (Eastern Cooperative Oncology Group) performance status 0-2

4. Progressing disease following all available chemotherapy treatment lines (including chemotherapy, bevacizumab+/-ziv-aflibercept, and an epidermal growth factor receptor (EGFR) inhibitor [if WT(wild type)-KRAS]

5. The central-radiologist's confirmation of PD* under the last (previous) line of "conventional treatment".

   * PD (progressive disease) by RECIST(Response Evaluation Criteria in Solid Tumors) criteria : a) there is 20% or more relative increment in the sum of diameters of target lesions in comparison with the base line sum, and their absolute increase is 5 mm. or more, or b) there appeared one or more new lesions, or c)there is substantial worsening in non-target disease

6. Age: between 18 and 85

7. Prior radiotherapy either as adjuvant treatment or for palliation is allowed, unless this was delivered to the only measurable lesion

8. Complete blood count reflecting adequate Bone Marrow:

Hb=/ > 9 g/dL, ANC=/> 1,500 Plt =/> 75,000/mcL; 9. Adequate liver function:

1. Total Bilirubin always =/<X1.5 ULN
2. ALT and AST and Alkaline Phosphatase =/ < 2.5 X upper normal limit , although in patients with liver metastases these are acceptable if =/< 5 X ULN; 11. Adequate renal function (serum creatinine): =/< 1.5 X ULN. 12. Absence of any non-hematological toxicity at grade 2 or higher. 13.The patient is able to understand and ready to sign the informed consent

Exclusion Criteria

1. Lack of confirmation of PD (under the pre-study treatment) by the central radiologist
2. Any concurrent other active cancer (except basal cell or squamous cell carcinoma of skin and early prostate cancer or DCIS- in situ breast cancer)
3. Inability to adhere to monthly visits to the oncological unit for evaluation
4. Presence of brain metastases
5. Continuous treatment with steroids or with NSAIDs or with anticoagulants during the last year (except micropirin)
6. Previous radiotherapy to the only site of measurable disease
7. Existence of active peptic ulcer or symptomatic coronary disease
8. Existence of chronic inflammatory diseases, such as ulcerative colitis or Crohn's disease or rheumatoid arthritis
9. Presence of ascites, and/or any other "third space" finding (eg. significant leg edema)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
capecitabine, cyclophosphamide, methotrexate, celecoxib	Capecitabine	The Investigational Product: Route and Dosage Form Ambulatory/oral, continuous but not uniform, DAILY treatment 1. Tab. CYCLOPHOSPHAMIDE 50mg, 1X1/day ONLY days 1-5 / week; At evening only (at the end of meal) 2. Tab. CAPECITABINE 500mg, fixed dose of 1500mg/day (1000mg at morning + 500mg at evening) ONLY on days 1-5 / week; At morning AND at evening (at the end of meals) 3. Tab. METHOTREXATE 2.5mg, 1x2/day ONLY on days 6-7/week; At morning AND evening (one hour before meal) 4. Tab. CELECOXIB 200 mg, 1x2/day EVERY day (at the end of meal)
capecitabine, cyclophosphamide, methotrexate, celecoxib	Cyclophosphamide	The Investigational Product: Route and Dosage Form Ambulatory/oral, continuous but not uniform, DAILY treatment 1. Tab. CYCLOPHOSPHAMIDE 50mg, 1X1/day ONLY days 1-5 / week; At evening only (at the end of meal) 2. Tab. CAPECITABINE 500mg, fixed dose of 1500mg/day (1000mg at morning + 500mg at evening) ONLY on days 1-5 / week; At morning AND at evening (at the end of meals) 3. Tab. METHOTREXATE 2.5mg, 1x2/day ONLY on days 6-7/week; At morning AND evening (one hour before meal) 4. Tab. CELECOXIB 200 mg, 1x2/day EVERY day (at the end of meal)
capecitabine, cyclophosphamide, methotrexate, celecoxib	Methotrexate	The Investigational Product: Route and Dosage Form Ambulatory/oral, continuous but not uniform, DAILY treatment 1. Tab. CYCLOPHOSPHAMIDE 50mg, 1X1/day ONLY days 1-5 / week; At evening only (at the end of meal) 2. Tab. CAPECITABINE 500mg, fixed dose of 1500mg/day (1000mg at morning + 500mg at evening) ONLY on days 1-5 / week; At morning AND at evening (at the end of meals) 3. Tab. METHOTREXATE 2.5mg, 1x2/day ONLY on days 6-7/week; At morning AND evening (one hour before meal) 4. Tab. CELECOXIB 200 mg, 1x2/day EVERY day (at the end of meal)
capecitabine, cyclophosphamide, methotrexate, celecoxib	Celecoxib	The Investigational Product: Route and Dosage Form Ambulatory/oral, continuous but not uniform, DAILY treatment 1. Tab. CYCLOPHOSPHAMIDE 50mg, 1X1/day ONLY days 1-5 / week; At evening only (at the end of meal) 2. Tab. CAPECITABINE 500mg, fixed dose of 1500mg/day (1000mg at morning + 500mg at evening) ONLY on days 1-5 / week; At morning AND at evening (at the end of meals) 3. Tab. METHOTREXATE 2.5mg, 1x2/day ONLY on days 6-7/week; At morning AND evening (one hour before meal) 4. Tab. CELECOXIB 200 mg, 1x2/day EVERY day (at the end of meal)

Primary Outcome Measures

Name	Time	Method
The median progression free survival (mPFS)	Base line and every consecutive 8 weeks, up to disease progression or exit from study for any other cause, up to 18 months.

Trial Locations

Locations (1)

Gastrointestinal Oncology Unit, Institute of Oncology, Davidoff Center, Rabin Medical Center, Belinson Campus,; 🇮🇱 Petach Tiqva, Israel