Clinical trial NCT01858571: Low Dose Chemotherapy Versus Best Supportive Care in Progressive Pediatric Malignancies
Official title: Low Dose Chemotherapy (Metronomic Therapy) Versus Best Supportive Care in Progressive and/or Refractory Pediatric Malignancies: a Double Blind Placebo Controlled Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malignant Childhood Neoplasm
Keywords: Childhood Cancer
Lead sponsor: All India Institute of Medical Sciences
Sponsor class: OTHER
First posted: 2013-05-21
Enrollment: 108
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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%.

Eligibility criteria: 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

Primary outcomes:
measure: Progression free survival
timeFrame: Up to 2 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Up to 2 years
Other outcomes:
measure: Quality of life
timeFrame: Up to 2 years
measure: Bio marker of angiogenesis (VEGF)
timeFrame: Up to 2 years
Locations:
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
state: Delhi
Study officials:
affiliation: All India Institute of Medical Sciences
name: Sameer Bakhshi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. 2023 Jun;13(2):234-237. doi: 10.1136/bmjspcare-2020-002731. Epub 2021 Jan 19.
citation: 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.