Dataset Information

Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

ABSTRACT:

Background

Calmangafodipir (CaM, PledOx) demonstrated efficacy in preventing patient-reported chemotherapy-induced peripheral neuropathy (CIPN) in a randomized phase 2 study in patients with metastatic colorectal cancer. The Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy (POLAR) program aimed to assess efficacy and safety of CaM in the prevention of CIPN in patients treated with oxaliplatin in adjuvant (POLAR-A, ClinicalTrials.gov.NCT04034355) or metastatic (POLAR-M, ClinicalTrials.gov.NCT03654729) settings.

Methods

Two randomized, placebo-controlled phase 3 trials investigated patient-reported, moderate-to-severe CIPN 9 months after beginning folinic acid, 5-fluorouracil, and oxaliplatin therapy with or without CaM. In POLAR-A, patients with stage III or high-risk stage II colorectal cancer were randomly assigned 1:1 to receive CaM 5 μmol/kg or placebo. In POLAR-M, patients with metastatic colorectal cancer were randomly assigned 1:1:1 to receive CaM 5 μmol/kg, CaM 2 μmol/kg, or placebo.

Results

POLAR-A (n = 301) and POLAR-M (n = 291) were terminated early following unexpected hypersensitivity reactions in CaM-treated patients. In a combined analysis of month 9 CIPN (primary endpoint) data from both trials (CaM 5 μmol/kg, n = 175; placebo, n = 176), 54.3% of patients in the CaM group had moderate-to-severe CIPN compared with 40.3% in the placebo group. The estimated relative risk for moderate-to-severe CIPN at month 9 was 1.37 (95% confidence interval = 1.01 to 1.86; P = .045). A higher proportion of patients experienced serious hypersensitivity reactions across both trials with CaM treatment (3.6%) than with placebo (0.8%).

Conclusion

The POLAR clinical studies failed to meet their primary endpoint. These results highlight the challenges of targeting oxidative stress for preventing CIPN in both the adjuvant and metastatic settings.

SUBMITTER: Pfeiffer P

PROVIDER: S-EPMC9678401 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

Pfeiffer Per P Lustberg Maryam M Näsström Jacques J Carlsson Stefan S Persson Anders A Nagahama Fumiko F Cavaletti Guido G Glimelius Bengt B Muro Kei K

JNCI cancer spectrum 20221101 6

<h4>Background</h4>Calmangafodipir (CaM, PledOx) demonstrated efficacy in preventing patient-reported chemotherapy-induced peripheral neuropathy (CIPN) in a randomized phase 2 study in patients with metastatic colorectal cancer. The Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy (POLAR) program aimed to assess efficacy and safety of CaM in the prevention of CIPN in patients treated with oxaliplatin in adjuvant (POLAR-A, ClinicalTrials.gov.NCT04034355) or metastatic (POLAR-M, C ...[more]

PMID: 36308441

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Project description:BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) has significant clinical impact on the quality of life for cancer patients and is a dose limiting toxicity. Trials studying preventive measures have been inconclusive. A systematic review and meta-analysis were conducted to evaluate the existing pharmacological and non-pharmacological interventions to prevent chronic OIPN.MethodsLiterature databases PubMed-MEDLINE, Embase and Scopus, were searched from 1 Jan 2005 to 08 Aug 2020 and major conferences' abstracts were reviewed for randomized controlled trials that examined the efficacy of any preventive measure for OIPN. The primary outcome measure was the incidence of chronic OIPN with a preventive intervention as compared to placebo or no intervention. The pooled risk ratio and its 95% confidence interval were calculated using a random effects model. A network meta-analysis was conducted to derive indirect evidence of any preventive effect of an intervention against placebo when original trials compared one intervention against another.ResultsForty-four trials were analyzed describing 29 chemoprotective interventions, including combinations, and 1 non-pharmacological intervention. Ratings were assessed via a combination of outcomes with quality assessment using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Of the 30 interventions examined, there were six interventions supporting potential efficacy, 11 interventions with insufficient evidence and 13 interventions not recommended.ConclusionCurrently, there is insufficient certainty to support any intervention as effective in preventing OIPN. Of note is that most of these studies have focused on pharmacological interventions; non-pharmacological interventions are underexplored. Further research on ways to limit OIPN is needed.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=225095, Prospero Registration Number: CRD42021225095.

Project description:BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.MethodsThe OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.DiscussionIf readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.Trial registrationClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Project description:IntroductionOxaliplatin remains the most widely used chemotherapeutic agent for treating advanced colorectal cancer but its efficacy is hampered by dose-limiting neurotoxicity manifested by a painful polyneuropathy. Oxaliplatin-induced peripheral neuropathy (OIPN) is characterised by acute and transient cold hyperaesthesia in the hours and days following oxaliplatin infusion (>90% of patients), but also by retarded chronic neuropathy due to the repetition of chemotherapy cycles (30-50% of patients). OIPN impairs the health-related quality of life (HRQOL) of patients and no preventive or curative strategies have as yet proven effective. A polyamine-reduced diet (PRD) has recently demonstrated its efficacy to prevent OIPN in animals without adverse effects.Methods and analysisThe NEUROXAPOL trial is a prospective, randomised, controlled, single-blind, monocentric and interventional study. This trial is aimed at evaluating the efficacy and feasibility of a PRD compared to a normal polyamine containing diet to prevent OIPN in patients treated by oxaliplatin-based chemotherapy. Patients (n=40 per group) will be randomly assigned to receive either a PRD or a normal diet before and during the chemotherapy regimen. The main objectives are to improve the cold pain thresholds, neuropathic pain symptoms, comorbidities (anxiety and depression) and HRQOL of patients. The primary end point is the assessment of cold pain thresholds 2 weeks after the third cycle of chemotherapy. The secondary end points are the evaluation of thermal pain thresholds, the grade of neuropathy, neuropathic pain, symptoms of anxiety and depression and HRQOL, until the 12th cycle of chemotherapy.Ethics and disseminationThe study was approved by an independent medical ethics committee 1 (CPP Sud Est 1, Saint Etienne, France) and registered by the competent French authority (ANSM, Saint Denis, France). The results will be disseminated in a peer-reviewed journal and presented at international congresses.Trial registration numberNCT01775449.

Dataset Information

Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

Background

Methods

Results

Conclusion

Publications

Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

Similar Datasets

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