Low Dose Chemotherapy Versus Best Supportive Care in Progressive Pediatric Malignancies

Low Dose Chemotherapy (Metronomic Therapy) Versus Best Supportive Care in Progressive and/or Refractory Pediatric Malignancies: a Double Blind Placebo Controlled Randomized Study

Many of the pediatric malignancies are not curable on progression on front line or 2nd line chemotherapy. Further therapy with conventional drugs imposes many side effects and decreases the QOL. The usual therapy offered to such patients is best supportive care.

Metronomic chemotherapy can induce tumor stabilization or tumor responses in patients with cancer that are refractory or have relapsed after conventional chemotherapy. Whether metronomic therapy is better than best supportive care is not known. In order to do so, a study is required which may compare metronomic therapy with a placebo therapy on PFS and QOL in relapsed refractory cases of pediatric solid tumors who have failed at least two lines of chemotherapy.

HYPOTHESIS

The investigators hypothesize that metronomic chemotherapy in progressive pediatric malignancy will improve PFS and QOL. If validated, then this form for therapy will be an option for both the patients and the clinicians, who are left with just an option of best supportive care in such situations of progressive pediatric cancers despite multiple lines of chemotherapy.

Study Overview

• Status: Completed
• Conditions: Malignant Childhood Neoplasm
• Intervention / Treatment: Drug: Low dose chemotherapy

Detailed Description

Many of the pediatric malignancies are not curable on progression on front line or 2nd line chemotherapy. Further therapy with conventional drugs imposes many side effects and decreases the QOL. The usual therapy offered to such patients is best supportive care.

Metronomic chemotherapy can induce tumor stabilization or tumor responses in patients with cancer that are refractory or have relapsed after conventional chemotherapy. Whether metronomic therapy is better than best supportive care is not known. In order to do so, a study is required which may compare metronomic therapy with a placebo therapy on PFS and QOL in relapsed refractory cases of pediatric solid tumors who have failed at least two lines of chemotherapy.

It will be double blind randomized study. One group will receive metronomic therapy along with best supportive care and other will receive placebo and best supportive care.

The treatment will be continued till progression is documented. Metronomic chemotherapy schedule : Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration) with each drug rounded off to the nearest tablet/capsule size.

Cycle A

• Daily oral Thalidomide (at 3mg/kg)
• Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg)
• Daily oral Etoposide (50 mg/m2/d) Cycle B
• Daily oral Thalidomide (at 3mg/kg)
• Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg)
• Daily oral Cyclophosphamide (2.5 mg/kg/d to a maximum of 100 mg/d) every 21 days

Placebo: Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration)

• Capsules of same size and color as used in metronomic therapy Best supportive care
• Management of pain as per WHO standard for pain management

The dose of medications in capsules have to be rounded off to the nearest capsule size. Instead of rounding off on the daily dose, the total dose over the week would be calculated and rounded off and divided over 5-6 days in a week. This is being done so as to prevent any extra dosing.

If any grade 3-4 toxicity occurs in the first course, then the dose for chemotherapy would be reduced in the subsequent course by 20%.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Refractory/Progressive non hematopoietic extracranial solid tumors following treatment with at least 2 lines of chemotherapy.
2. ECOG performance status (<=3)(at least patients ambulating with crutches or on wheel chair)
3. Age: 5-18 years
4. Recovered from all acute toxic effects of earlier therapy
5. Absolute neutrophil count > 1X 109/L
6. Absolute platelet count > 75 x 109/L
7. Normal renal functions
8. Serum bilirubin <1.5 times the upper limit of normal, and the serum aspartate aminotransferase and alanine aminotransferase < 5 times the upper limit of normal.

Exclusion Criteria:

1. Uncontrolled concurrent illness or active infection
2. Positive serology for human immunodeficiency.
3. Unable to swallow oral medication
4. Pregnant and breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose chemotherapy; Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration) with each drug rounded off to the nearest tablet/capsule size. Cycle A; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Etoposide (50 mg/m2/d) Cycle B; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Cyclophosphamide (2.5 mg/kg/d to a maximum of 100 mg/d) every 21 days	Drug: Low dose chemotherapy; Metronomic chemotherapy schedule : Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration) with each drug rounded off to the nearest tablet/capsule size. Cycle A; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Etoposide (50 mg/m2/d) Cycle B; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Cyclophosphamide (2.5 mg/kg/d to a maximum of 100 mg/d) every 21 days; Other Names: •Thalidomide •Celecoxib •Etoposide •Cyclophosphamide
Placebo Comparator: Best supportive care; Placebo: Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration); Capsules of same size and color as used in metronomic therapy Best supportive care; Management of pain as per WHO standard for pain management	Drug: Low dose chemotherapy; Metronomic chemotherapy schedule : Alternating cycles of Cycle A and B (Each cycle includes 3 weeks of drug administration) with each drug rounded off to the nearest tablet/capsule size. Cycle A; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Etoposide (50 mg/m2/d) Cycle B; Daily oral Thalidomide (at 3mg/kg); Daily oral Celecoxib (100 mg BID for patients < 20 kg, 200 mg BID for patients 20-50 kg, and 400 mg BID for patients > 50 kg); Daily oral Cyclophosphamide (2.5 mg/kg/d to a maximum of 100 mg/d) every 21 days; Other Names: •Thalidomide •Celecoxib •Etoposide •Cyclophosphamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	Up to 2 years

Other Outcome Measures

Outcome Measure	Time Frame
Quality of life	Up to 2 years
Bio marker of angiogenesis (VEGF)	Up to 2 years

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, New Delhi
• Investigators: Principal Investigator: Sameer Bakhshi, MD, All India Institute of Medical Sciences, New Delhi

Publications and helpful links

General Publications

• Pramanik R, Agarwala S, Sreenivas V, Dhawan D, Bakhshi S. Quality of life in paediatric solid tumours: a randomised study of metronomic chemotherapy versus placebo. BMJ Support Palliat Care. 2021 Jan 19:bmjspcare-2020-002731. doi: 10.1136/bmjspcare-2020-002731. Online ahead of print.
• Pramanik R, Agarwala S, Gupta YK, Thulkar S, Vishnubhatla S, Batra A, Dhawan D, Bakhshi S. Metronomic Chemotherapy vs Best Supportive Care in Progressive Pediatric Solid Malignant Tumors: A Randomized Clinical Trial. JAMA Oncol. 2017 Sep 1;3(9):1222-1227. doi: 10.1001/jamaoncol.2017.0324.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: May 17, 2013
• First Submitted That Met QC Criteria: May 20, 2013
• First Posted (Estimate): May 21, 2013

Study Record Updates

• Last Update Posted (Estimate): January 25, 2017
• Last Update Submitted That Met QC Criteria: January 24, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Childhood Cancer
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cyclooxygenase 2 Inhibitors; Cyclophosphamide; Etoposide; Thalidomide; Celecoxib
• Other Study ID Numbers: IEC/NP-63/2013

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No