Trial Outcomes & Findings for Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M) (NCT NCT03654729)

Last Updated: 2021-12-17

Results Overview

Percentage of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

291 participants

Primary outcome timeframe

9 months

Results posted on

2021-12-17

Participant Flow

Patients were recruited in the US, EU and Asia between 2018 and 1 March 2020. The Sponsor placed recruitment/dosing in the POLAR program on hold following interactions with the French regulatory authority and a US clinical hold of the study on 23 January 2020. As of 2 March 2020, no more patients were enrolled or IMP administered. Enrolled patients were followed until the data cut-off date of 31 August 2020 and these patients have been assigned as "completed" in the disposition.

386 patients were screened in the 28 days before the start of treatment, 291 were randomised and 285 were treated.

Participant milestones

Participant milestones
Measure	PledOx (2 µmol/kg) Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Overall Study STARTED	97	96	98
Overall Study Treated	96	93	96
Overall Study COMPLETED	66	70	69
Overall Study NOT COMPLETED	31	26	29

Reasons for withdrawal

Reasons for withdrawal
Measure	PledOx (2 µmol/kg) Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Overall Study Death	9	9	16
Overall Study Withdrawal by Subject	8	6	4
Overall Study Study terminated by Sponsor	3	5	4
Overall Study Not reported	2	4	5
Overall Study Progressive disease	3	0	0
Overall Study Lost to Follow-up	2	0	0
Overall Study Physician Decision	2	0	0
Overall Study Protocol Violation	1	1	0
Overall Study Non-compliance with study drug	0	1	0
Overall Study Site terminated by Sponsor	1	0	0

Baseline Characteristics

Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PledOx (2 µmol/kg) n=96 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=93 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=96 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial	Total n=285 Participants Total of all reporting groups
Age, Continuous	63.5 years STANDARD_DEVIATION 10.5 • n=5 Participants	62.9 years STANDARD_DEVIATION 9.6 • n=7 Participants	61.6 years STANDARD_DEVIATION 12.4 • n=5 Participants	62.7 years STANDARD_DEVIATION 10.9 • n=4 Participants
Sex: Female, Male Female	36 Participants n=5 Participants	43 Participants n=7 Participants	40 Participants n=5 Participants	119 Participants n=4 Participants
Sex: Female, Male Male	60 Participants n=5 Participants	50 Participants n=7 Participants	56 Participants n=5 Participants	166 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	41 Participants n=5 Participants	40 Participants n=7 Participants	39 Participants n=5 Participants	120 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	49 Participants n=5 Participants	45 Participants n=7 Participants	51 Participants n=5 Participants	145 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	6 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	18 Participants n=4 Participants
Body Mass Index	23.60 kg/m^2 n=5 Participants	24.20 kg/m^2 n=7 Participants	24.00 kg/m^2 n=5 Participants	24.00 kg/m^2 n=4 Participants
ECOG performance status 0	65 Participants n=5 Participants	62 Participants n=7 Participants	53 Participants n=5 Participants	180 Participants n=4 Participants
ECOG performance status 1	31 Participants n=5 Participants	31 Participants n=7 Participants	41 Participants n=5 Participants	103 Participants n=4 Participants
ECOG performance status Unknown	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants

PRIMARY outcome

Timeframe: 9 months

Population: Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria: * the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or * the 3 month Assessment Visit occurred prior to 1 Mar 2020, or * the patient received the 6th cycle of IMP after 1 Mar 2020.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=54 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=55 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=57 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)	31 Participants	27 Participants	25 Participants

SECONDARY outcome

Timeframe: 9 months

Percentage of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=54 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=55 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=57 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)	43 Participants	40 Participants	42 Participants

SECONDARY outcome

Timeframe: Baseline and 8 weeks

Mean change from baseline in sensitivity to touching cold items on day 2, Cycle 4 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity Questionnaire (measuring sensitivity when touching or swallowing cold objects/fluid). 10 point scale from 0 meaning no sensitivity/discomfort at all to 10 meaning sensitivity/discomfort as bad as it can be.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=68 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=66 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=66 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Sensitivity to Touching Cold Items	3.88 Scores on a scale Interval 3.19 to 4.57	4.13 Scores on a scale Interval 3.43 to 4.82	3.41 Scores on a scale Interval 2.71 to 4.11

SECONDARY outcome

Timeframe: 9 months

Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=80 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=78 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=78 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Cumulative Dose of Oxaliplatin During Chemotherapy	780.69 mg/m^2 Interval 711.86 to 849.52	803.54 mg/m^2 Interval 734.01 to 873.07	764.52 mg/m^2 Interval 694.91 to 834.14

SECONDARY outcome

Timeframe: Baseline and 9 months

Mean change from baseline in vibration sense, on the lateral malleolus (left and right), using a graduated tuning fork, at 9 months after the first dose of IMP. When the tuning fork was struck against the ball of the thumb, the base of the tuning fork was placed over the appropriate bony surface (i.e., lateral malleolus left and right) and the patient was asked to indicate the moment when the vibration was no longer detected. The intensity at which the patient no longer detected the vibration is reported on a scale of 0 (minimum score, representing the maximum vibration amplitude) to 8 (maximum score, representing the minimum vibration amplitude)

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=49 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=49 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=51 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Vibration Sensitivity on the Lateral Malleolus	-1.53 Scores on a scale Standard Deviation 2.06	-1.61 Scores on a scale Standard Deviation 2.09	-1.36 Scores on a scale Standard Deviation 1.68

SECONDARY outcome

Timeframe: Baseline and 9 months

Mean change from baseline in worst pain in hands or feet in the past week, using the Pain Assessment (Numerical Rating Scale (NRS)), at 9 months after the first dose of IMP. The NRS is a 10 point scale with 0 as no pain at all and 10 as pain as bad as you can imagine and evaluates the intensity of pain in hands and feet during the past week. A higher value means worse outcome.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=51 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=52 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=54 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Worst Pain in Hands or Feet	2.19 Scores on a scale Interval 1.37 to 3.01	1.58 Scores on a scale Interval 0.76 to 2.39	1.92 Scores on a scale Interval 1.12 to 2.72

SECONDARY outcome

Timeframe: Baseline and 9 months

Mean change from baseline in the time to complete the grooved Pegboard with the non-dominant hand, at 9 months after the first dose of IMP.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=45 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=47 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=50 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Functional Impairment (in the Non-dominant Hand)	9.68 seconds Interval -3.07 to 22.44	14.24 seconds Interval 1.72 to 26.75	12.01 seconds Interval -0.07 to 24.09

SECONDARY outcome

Timeframe: 12, 15 and 18 months

Population: The safety analysis set consisting of all randomized patients who received at least one dose of IMP. The overall number analyzed represents the total in the safety population treated at the start of the study. ORR was assessed throughout the study when varying numbers of patients in each group remained on study

Percentage of patients with an overall response (complete response or partial response) according to RECIST v1.1 for target lesions and assessed by CT (preferred) or MRI. Complete response=disappearance of all target lesions; partial response \>=30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=96 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=93 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=96 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Overall Response Rate (ORR) Month 18 · No	2 Participants	3 Participants	0 Participants
Overall Response Rate (ORR) Month 18 · Yes	1 Participants	0 Participants	1 Participants
Overall Response Rate (ORR) Month 12 · Missing	22 Participants	19 Participants	19 Participants
Overall Response Rate (ORR) Month 12 · No	6 Participants	13 Participants	12 Participants
Overall Response Rate (ORR) Month 12 · Yes	13 Participants	12 Participants	8 Participants
Overall Response Rate (ORR) Month 15 · Missing	9 Participants	14 Participants	7 Participants
Overall Response Rate (ORR) Month 15 · No	7 Participants	7 Participants	3 Participants
Overall Response Rate (ORR) Month 15 · Yes	6 Participants	2 Participants	2 Participants
Overall Response Rate (ORR) Month 18 · Missing	1 Participants	3 Participants	1 Participants

SECONDARY outcome

Timeframe: Analyses at 12 and 24 months were planned; the analysis was performed once based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor

Population: Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received.

Patients with progression-free survival

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=95 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=93 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=95 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Progression-free Survival (PFS)	40 participants	36 participants	36 participants

SECONDARY outcome

Timeframe: An analysis at 36 months was planned. The analysis was performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor

Population: Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received.

Patients with overall survival

Outcome measures

Outcome measures
Measure	PledOx (2 µmol/kg) n=95 Participants Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	PledOx (5 µmol/kg) n=93 Participants Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo n=95 Participants Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Overall Survival (OS)	9 participants	9 participants	16 participants

Adverse Events

PledOx (2 µmol/kg)

Serious events: 27 serious events

Other events: 93 other events

Deaths: 9 deaths

PledOx (5 µmol/kg)

Serious events: 21 serious events

Other events: 91 other events

Deaths: 9 deaths

Placebo

Serious events: 24 serious events

Other events: 95 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Kristina Sjoblom Nygren

Egetis Therapeutics AB

Phone: +46732344698

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place