Clinical trial NCT02679443: Vitamin Supplementation in NSCLC Patients on Pemetrexed Based Chemotherapy
Official title: Optimum Duration of Vitamin B12 and Folate Supplementation in Non-squamous Non-small Cell Lung Cancer (NSCLC) Patients Undergoing Pemetrexed Containing Chemotherapy: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Lung Adenocarcinoma
Neutropenia
Anemia
Thrombocytopenia
Nonsquamous Nonsmall Cell Neoplasm of Lung
Keywords: Lung Adenocarcinoma
Non-squamous NSCLC
Chemotherapy
Pemetrexed
Vitamin B12
Folate
Supplementation
Cytopenia
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2016-02-10
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Folic acid (FA; folate) in the dose of 350-1,000 μg daily should be supplemented, daily, starting 7 days before the first dose of pemetrexed based chemotherapy and should be continued while the patient is on therapy and for 21 days after cessation of therapy. Vitamin B12 injections (1,000 μg i.m.) should also be started 1 week before the first dose of chemotherapy. However, the evidence for delaying chemotherapy by seven days for the purpose of giving vitamin B12 and FA supplementation is not robust. Observational and prospective single arm studies have not shown any increased toxicity if pemetrexed was started earlier than the recommended duration of supplementation. In a resource constrained setting, this will lead to one additional visit and 1-week chemotherapy delay which may be inconvenient for patients.

Hence an open label, randomized control trial is being undertaken to evaluate if there are any differences in pemetrexed related hematological toxicity amongst patients who receive delayed initiation of chemotherapy (following 5 - 7 days of vitamin B12 and FA supplementation; Delayed Arm) as compared to those in whom vitamin B12 and FA supplementation is starting simultaneously (within 24 hours) of initiation of chemotherapy (Immediate Arm).

Detailed description: Chemotherapy Regimen:

All patients will receive pemetrexed and cisplatin in doses of 500 mg and 65 mg, respectively, per square meter of body surface area each on day 1 of a 3-week cycle. Patients with contraindications to administration of cisplatin, those who are intolerant to cisplatin, or develop grade 3 or 4 adverse events from cisplatin will be given carboplatin in combination with pemetrexed. Carboplatin will be given at a dose calculated to produce an area under the concentration-time curve (AUC) of 5.0mg/mL/min. Dose modifications of either pemetrexed or the platinum agent or both will be done in case of significant change in PS or toxicity from or intolerance to dose administered in the previous cycle.

Supplementation:

1. Folic acid (FA) supplementation will be given to all patients orally in the dose of 5 ml (1000 μg) once daily of VITCOFOL (FDC Limited, Mumbai, India) pediatric formulation, which contains 200 μg FA/ml of the preparation. Patients will be instructed to measure the prescribed dose using a 5 ml plastic syringe containing markings at every 0.5 ml. Patients will also be instructed not to take any additional multivitamin supplements. In addition to FA supplementation, all patients will also be started simultaneously on oral iron (ferrous sulphate 200 mg twice a day). Once initiated, both FA and ferrous sulphate will be given on a daily basis and continued throughout the duration of chemotherapy and for at least 3 weeks beyond the last cycle.
2. Vitamin B12 supplementation will be given to all patients intramuscularly in the dose of 1000 μg along with each cycle of chemotherapy (maximum of six doses during the study period).

Eligibility criteria: Inclusion Criteria:

* Locally advanced or metastatic (Stage IIIB/IV) NSCLC and Stage III A NSCLC, not scheduled for upfront surgical resection
* Nonsquamous histology (including adenocarcinoma)
* At least one unidimensionally measurable lesion, according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0), or at least one nonmeasurable lesion that was assessable using conventional techniques or a spiral computed tomography scan
* An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
* No previous chemotherapy for advanced disease and no previous targeted molecular therapy
* Adequate liver and renal function;
* Previous radiation therapy is permitted if completed \>4 weeks before enrollment and the patient has recovered from any treatment-related toxicity.

Exclusion Criteria:

* Hemoglobin value \< 9gm/dl
* Required erythropoiesis stimulating agents or blood transfusions in the recent past (4 months)
* Symptomatic untreated brain metastasis
* Any previous malignancy
* Concurrent use of any other tumor therapy
* Active infection or a serious concomitant disorder
* Inability to interrupt nonsteroidal anti-inflammatory agents
* Inability or unwillingness to take folic acid, vitamin B12, or dexamethasone supplementation
* Pregnancy or breast feeding

Primary outcomes:
measure: Incidence of any grade hematological toxicity
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
Secondary outcomes:
measure: Incidence of grade 3/4 hematological toxicity
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
measure: Number of doses of G-CSF administered
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
measure: Number of doses of ESAs administered
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
measure: Number of PRBC transfusions administered
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
measure: Relative Dose Intensity (RDI) delivered
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
measure: Number of Inter-Cycle Delays (ICDs)
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
Other outcomes:
measure: Changes in serum levels of folic acid and homocysteine
timeFrame: Completion of six cycles (average of 18 weeks; each cycle is 21 days) of pemetrexed-platinum doublet chemotherapy
Locations:
city: Chandigarh
country: India
facility: PGIMER
Study officials:
affiliation: PGIMER, Chandigarh
name: Navneet Singh, MD DM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Singh N, Baldi M, Kaur J, Muthu V, Prasad KT, Behera D, Bal A, Gupta N, Kapoor R. Timing of folic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: The PEMVITASTART randomized trial. Cancer. 2019 Jul 1;125(13):2203-2212. doi: 10.1002/cncr.32028. Epub 2019 Mar 2.
citation: Baldi M, Behera D, Kaur J, Kapoor R, Singh N. Rationale and Design of PEMVITASTART-An Open-label Randomized Trial Comparing Simultaneous Versus Standard Initiation of Vitamin B12 and Folate Supplementation in Nonsquamous, Non-Small-cell Lung Cancer Patients Undergoing First-line Pemetrexed-based Chemotherapy. Clin Lung Cancer. 2017 Jul;18(4):432-435. doi: 10.1016/j.cllc.2016.11.017. Epub 2016 Dec 2.