Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx<sup>®</sup>): a placebo-controlled randomised phase II study (PLIANT)

Glimelius, Bengt; Manojlovic, Nebojsa; Pfeiffer, Per; Mosidze, Baadur; Kurteva, G.; Karlberg, Mia; Mahalingam, Devalingam; Jensen, Peter Buhl; Kowalski, Jan; Bengtson, Marie Helene; Nittve, Malin; Näsström, Jacques

doi:10.1080/0284186x.2017.1398836

Cited by 74 publications

(74 citation statements)

References 49 publications

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“…Calmangafodipir, derived from a magnetic resonance imaging contrast agent known as mangafodipir, mimics the mitochondrial enzyme manganese superoxide dismutase, which reduces reactive oxygen species and subsequent nerve injury after platinum‐based chemotherapy exposure . In a placebo‐controlled, double‐blinded randomized phase II study in patients with metastatic colorectal cancer, calmangafodipir reduced CIPN associated symptoms during and after treatment . Two international trials, POLAR A and POLAR M, are currently evaluating the efficacy of calmangafodipir for the prevention of oxaliplatin‐induced neuropathy in colorectal cancer patients.…”

Section: Prevention Of Pipn: Clinical Trial Strategiesmentioning

confidence: 99%

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Staff

Cavaletti

Islam

et al. 2019

J Peripheral Nervous Sys

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Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. PIPN includes acute neurotoxicity restricted to oxaliplatin, and chronic non-length-dependent sensory neuronopathy with positive and negative sensory symptoms and neuropathic pain in both upper and lower limbs.Chronic sensory axonal neuropathy manifesting as stocking-and-glove distribution is also frequent. Worsening of neuropathic symptoms after completing the last chemotherapy course may occur. Motor and autonomic involvement is uncommon. Ototoxicity is frequent in children and more commonly to cisplatin. Platinum-based compounds result in more prolonged neuropathic symptoms in comparison to other chemotherapy agents. Patient reported outcomes questionnaires, clinical evaluation and instrumental tools offer complementary information in PIPN. Electrodiagnostic features include diffusely reduced/abolished sensory action potentials, in keeping with a sensory neuronopathy. PIPN is dependent on cumulative dose but there is a large variability in its occurrence. The search for additional risk factors for PIPN has thus far yielded no consistent findings. There are currently no neuroprotective strategies to reduce the risk of PIPN, and symptomatic treatment is limited to duloxetine that was found effective in a single phase III intervention study. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of PIPN.

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Section: Prevention Of Pipn: Clinical Trial Strategiesmentioning

confidence: 99%

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Staff

Cavaletti

Islam

et al. 2019

J Peripheral Nervous Sys

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“…Karlsson and Jynge as innovators of the therapy and founders of PledPharma AB may be eager to see that calmangafodipir can be available for clinical use as soon as possible and that they feel confident that it will work in patients. This does not surpass the requirements to conduct studies in the order they should be done with regards to regulatory requirements (phase I followed by phase II, now reported in the publication [2], and finally phase III). The PLIANT study was properly designed and executed, and it could show clinically meaningful gains (about a 40% relative reduction) in prevention of a disabling adverse effect from oxaliplatin, OIPN [9,10].…”

Section: Discussionmentioning

confidence: 98%

“…2017;5:1-10. [2] Yri OE, Vig J, Hegstad E, et al We thank Karlsson and Jynge for their letter [1] to the article published in Acta Oncologica about the results of the placebo-controlled study PLIANT [2], exploring the neuroprotective effects of calmangafodipir in oxaliplatin-treated patients with metastatic colorectal cancer (mCRC), and the possibilities to respond to the issues raised. 1.…”

Section: Disclosure Statementmentioning

confidence: 99%

The PLIANT trial gives trustworthy data

2018

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“…The third reason for less OIPN might emerge if effective neuroprotectors that, at the same time, do not prevent the anti-tumor effects of oxaliplatin, can be developed. Through the years, many attempts have been done, such as calmangafodipir [22], but none has so far been approved for use [23].…”

Section: How Much Less Is Seen If 3 Months Of Oxaliplatin Is Given?mentioning

confidence: 99%

“…BG was the principal investigator of the neuroprotective PLIANT trial (22) supported by PledPharma AB, Sweden. No potential conflict of interest was reported by PN.…”

Section: Disclosure Statementmentioning

confidence: 99%

Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer

Glimelius

Nygren

2019

Acta Oncologica

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The addition of oxaliplatin to a fluoropyrimidine is reference treatment after colon cancer surgery in patients with stage III and in stage II if at least one high-risk criterium for recurrence is present [1-3]. Even if guidelines open for using a fluoropyrimidine alone, there is a tendency to add oxaliplatin whenever adjuvant chemotherapy is indicated, at least in stage III. Three randomized trials comparing adjuvant therapy for six months using a fluoropyrimidine with or without oxaliplatin showed that the combination improved disease-free survival (DFS) by approximately 20% (hazard ratios, HRs 0.80-0.82) [4-6]. Overall survival was also slightly improved (HRs 0.84-0.88). An average risk of recurrence of 30% after fluoropyrimidine treatment alone, typical for many stage III patients, means that six additional patients per 100 treated will not experience any recurrence if oxaliplatin was added. If the recurrence risk is higher, more treated patients are gained, but for many stage III patients, including most patients with stage II and high-risk criteria, the recurrence risk is less, and the gain from adding oxaliplatin is only a few percent. All treated patients are at risk of toxicity, including the oxaliplatin-induced chronic and often disabling neurotoxicity. The oxaliplatin-induced peripheral neuropathy (OIPN) was considered along with the gains in recurrence risk and survival when different scientific and clinical organizations such as ASCO and NCCN in the US and ESMO in Europe and national groups recommended an oxaliplatin combination for all stage III colon cancers and for stage II cancers with high-risk factors. The extent of the adverse effects, i.e. the downside of adding oxaliplatin was known from the clinical trials where the treating physicians graded the neurotoxicity according to one of a few recommended scales. Typically, acute peripheral neurotoxicity of grade 2 or higher was recorded in 30-50% of the patients and although chronic OIPN was seen, it was not considered extensive [4-6]. In the MOSAIC trial, grade 2 and 3 chronic neuropathy were seen in 4.8 and 1.3%, respectively, after 12 months and in 3.4 and 0.7%, respectively, after 4 years [4].

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Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx^®): a placebo-controlled randomised phase II study (PLIANT)

Abstract: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.

Cited by 74 publications

References 49 publications

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

The PLIANT trial gives trustworthy data

Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer

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Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx®): a placebo-controlled randomised phase II study (PLIANT)

Abstract: Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.

Cited by 74 publications

References 49 publications

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

Platinum‐induced peripheral neurotoxicity: From pathogenesis to treatment

The PLIANT trial gives trustworthy data

Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer

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Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx^®): a placebo-controlled randomised phase II study (PLIANT)