Efficacy and safety of Tanezumab in patients with bone metastasis
Research type
Research Study
Full title
A Phase 3 Randomised, Double-Blind, Placebo-Controlled, Multicenter Study of the Analgesic Efficacy and Safety of Subcutaneous Administration of Tanezumab (PF-04383119) in Subjects with Cancer Pain Predominantly Due to Bone Metastasis receiving Background Opioid Therapy
IRAS ID
188900
Contact name
Marie Fallon
Contact email
Sponsor organisation
Pfizer Inc.,235 East 42nd Street, New York, NY 10017
Eudract number
2013-002223-42
Duration of Study in the UK
3 years, 4 months, 3 days
Research summary
Research Summary
This study is investigating an experimental drug called Tanezumab (PF-04383119) that is being developed for use in moderate to severe chronic pain conditions. The purpose of this research study is to compare the effects of this investigational study drug with a placebo to find out which is better for treating pain caused by bone metastases.
Approximately 255 patients from about 18 countries who meet the eligibility requirements will take part in this study. Patients will be randomly assigned 1:1:1 (approximately 85 patients per group)to receive one of two doses of investigational drug PF-04383119 (10mg or 20 mg) or matching placebo. A total of 3 subcutaneous injections will be given, separated by 8 weeks in addition to background opioids administered throughout the study.
Patients will be expected to participate in this research study for just over 1 year. The study will consist of a Pre Treatment Period (which can last up to 37 days), a 6-month Treatment Period, and a 6 month Follow-Up Period..In addition, subjects who were randomised and treated in Tanezumab Study A4091061 (regardless of treatment group) and who subsequently underwent a total knee, hip or shoulder replacement during participation in the study (treatment period or safety follow-up period) will be asked to take a part in the sub-study (a long-term observational study). There are no study medications in this observational study. The purpose of this sub-study is to gather information on pain, function, satisfaction and additional or corrective procedures.
This sub-study is designed with a total duration of subject follow-up of 24 weeks after the total joint replacement surgery. The exact number of patients that will take part in this sub-study is not known, but it is expected to be less than 25.Summary of Results
Subject Disposition and Demography:
A total of 325 subjects were screened for the study, of which 156 subjects were randomized; 155 subjects were treated, and one subject randomized to placebo was not treated. Of the randomized subjects, 74 subjects were randomized to Placebo group, 10 subjects were randomized to tanezumab 10 mg treatment group, and 72 subjects were randomized to tanezumab 20 mg treatment group. One subject who was randomized to the tanezumab 10 mg treatment group later received tanezumab 20 mg for any remaining doses (tanezumab 10/20 treatment group) after the implementation of Protocol Amendment 3.A total of 77 subjects (49.7%) completed the Treatment Period: (ie, up to Week 24) and of those, 62 subjects (40.0%) completed the Safety Follow up Period. Of those who discontinued from the Treatment Period (78 subjects [50.3%]), few completed the Safety Follow-up Period (3 subjects [1.9%]). The proportion of subjects who completed the Treatment Period was comparable for the tanezumab 20 mg (36 subjects [50.0%]) and placebo treatment groups (36 subjects [49.3%]).
One subject who had a TJR agreed to participate in the substudy.
Two subjects discontinued treatment and from the study due to travel restrictions related to the Coronavirus Disease 2019 (COVID-19) pandemic.
Overall, demographic characteristics were balanced across tanezumab 20 mg and placebo treatment groups except for gender and some age categories. There were more male subjects (46 subjects [63.9%] vs 34 subjects [46.6%]) in tanezumab 20 mg treatment group compared with the placebo treatment group. The mean age was similar in the tanezumab 20 mg and placebo treatment groups. However, the proportion of subjects in the 45 to 64 years age group was lower in the tanezumab 20 mg treatment group than the placebo treatment group (45.8% vs 60.3%) and the proportion of subjects in the ≥65 years age group was higher in the tanezumab 20 mg treatment group than in the placebo treatment group (50.0% vs 26.0%).
Overall, racial groups were well balanced in the placebo and tanezumab 20 mg treatment groups.
Efficacy Results:
Primary Endpoint Results
Treatment with tanezumab 20 mg resulted in significant improvement from Baseline to Week 8 in the daily average pain intensity at the index cancer pain site compared with placebo treatment and met the primary objective of the study Results of a sensitivity analysis of the primary endpoint that repeated the primary analysis using data prior to the COVID-19 pandemic (least squares [LS] mean difference: -0.55) were directionally consistent with the primary analysis (LS mean difference: -0.78); however, the results were not significant (p=0.1870).Secondary Endpoint Results
• Change from Baseline in the Daily Average Pain Intensity in the Index Bone
Metastasis Cancer Site: Tanezumab 20 mg treatment resulted in significant improvement from Baseline in the daily average pain intensity at the index cancer pain site compared with placebo at Weeks 1, 2, 4, and 6. From Weeks 12 to 24, tanezumab 20 mg treatment resulted in a numerical reduction from Baseline in the daily average pain intensity at the index cancer pain site compared with placebo, but the difference was not significant at any of these time points. Treatment differences from Weeks 12 to 24 were directionally consistent with the treatment difference at Week 8, but lower in magnitude. At Week 8, there were 58 and 62 subjects in the placebo and tanezumab 20 mg treatment groups, respectively. At Week 24, there were 38 and 41 subjects in the placebo and tanezumab 20 mg treatment groups, respectively.
• Change from Baseline in the Daily Worst Pain Intensity in the Index Bone
Metastasis Cancer Site: Tanezumab 20 mg treatment resulted in significant improvement from Baseline in the daily worst pain intensity at the index cancer pain site compared with placebo at Weeks 2, 4, and 6. From Weeks 8 to 24, tanezumab 20 mg treatment resulted in numerical reduction from Baseline in the daily worst pain intensity at the index cancer pain site compared with placebo, but the difference was not significant at any of these time points.
• Change from Baseline in the Weekly Average Pain Intensity in Non-index Cancer Pain Sites: Non-index cancer pain sites selected by the subject were pain confirmed by the Investigator to be due to cancer or cancer treatment, and the pain was judged by the Investigator to be somatic, neuropathic, or visceral in nature. One subject reported non-index visceral cancer pain. Tanezumab 20 mg treatment resulted in numerical reduction from Baseline in the weekly average pain intensity in non-index cancer pain sites compared with placebo at Weeks 1 through 24, but the treatment difference was not significant at any time point. At Weeks 8 and 24, treatment differences in the non-index cancer pain sites were directionally consistent with those in the index cancer pain site. For subjects with a Baseline score ≥5, tanezumab 20 mg treatment resulted in numerical reduction from Baseline in the weekly average pain intensity in non-index cancer pain sites compared with placebo at Weeks 1 through 24, but the treatment difference was not significant at any time point.
• Change from Baseline in the Weekly Worst Pain Intensity in Non-index Cancer Pain Sites: Tanezumab 20 mg treatment resulted in significant improvement from Baseline in the weekly worst pain intensity at the non-index cancer pain sites compared with placebo at Weeks 2, 4, and 16 (p≤0.0410). At Weeks 1, 6, 8, 12, and 24, tanezumab 20 mg treatment resulted in numerical reduction from Baseline in weekly worst pain intensity at the non-index cancer pain sites compared with placebo, but the treatment difference was not significant at any of these time points. For subjects with a Baseline score ≥5, tanezumab 20 mg treatment resulted in significant improvement from Baseline in the weekly worst pain intensity at the non-index cancer pain sites compared with placebo at Weeks 2, 4, 12, 16, and 24 (p≤0.0460).
• Change from Baseline in the Brief Pain Inventory – Short Form (BPI-sf): For both the change from Baseline in BPI-sf average and worst pain scores, there was an improvement (reduction) from Baseline in the tanezumab 20 mg treatment group compared with the placebo treatment group at all time points. Tanezumab 20 mg treatment resulted in significant improvement in the average pain BPI-sf score compared with placebo at Weeks 4 and 8 (p=0.0244 and p=0.0401, respectively) and in the worst pain BPI-sf score compared with placebo at Weeks 4 and 24 (p=0.0355 and p=0.0438, respectively). Tanezumab 20 mg treatment resulted in significant improvement from Baseline in the BPI‑sf pain interference index compared with placebo at Week 8 (p=0.0462). At Weeks 2, 4, 6, 16, and 24, tanezumab 20 mg treatment resulted in numerical reduction from Baseline in the BPI-sf pain interference index compared with placebo, but the difference was not significant at any of these time points. Tanezumab 20 mg treatment resulted in significant improvement compared with placebo for the BPIsf individual scores of pain interference with general activity at Week 8 (p=0.0145) and pain interference with sleep at Week 4 (p=0.0450); numerical reduction was observed at all other time points. Tanezumab 20 mg treatment resulted in numerical reduction for all other BPI-sf individual scores (walking ability, normal work, mood, relations with other people, and enjoyment of life) compared with placebo at all time points, except for relations with other people at Week 2 (LS mean difference [SE]: 0.18 [0.40]).
• Percent Reduction From Baseline in Daily Average and Worst Pain Intensity in the Index Bone Metastasis Cancer Pain Site: Tanezumab 20 mg treatment was associated with a numerical increase in the proportion of responders in daily average and worst pain intensity at the index cancer pain site at all levels (≥30%, ≥50%, ≥70%, and ≥90%) at all weeks compared with placebo (except Week 1, ≥90%). Tanezumab 20 mg treatment was associated with a significant increase in the proportion of responders in daily average and worst pain intensity pain intensity in the index cancer pain site compared with placebo for the ≥50% response level at Week 8 (p=0.0405 and p=0.0457, respectively). Tanezumab 20 mg treatment was also associated with a significant increase in the proportion of responders in daily average pain intensity in the index cancer pain site compared with placebo for the ≥50% response level at Weeks 2, 4, and 6 and for the ≥70% response level at Weeks 4 and 6. Additionally, tanezumab 20 mg treatment was associated with a significant increase in the proportion of responders in daily worst pain intensity in the index cancer pain site compared with placebo for the ≥50% response level at Weeks 4 and 6 and for the ≥30% response level at Weeks 6, 16, and 24.
• Change from Baseline in PGA of Cancer Pain: Tanezumab 20 mg treatment resulted in significant improvement from Baseline in PGA of Cancer Pain compared with placebo at Week 4 (p=0.0402), using multiple imputation. At Weeks 2, 6, 8, 16, and 24, tanezumab 20 mg treatment resulted in numerical reduction from Baseline in PGA of Cancer Pain compared with placebo, but the treatment difference was not significant at any of these time points.
• Improvement of at least Two Points in PGA of Cancer Pain: Treatment with tanezumab 20 mg was associated with a numerical increase in the proportion of subjects reporting a ≥2-point reduction from Baseline in PGA of Cancer Pain compared with placebo treatment at Weeks 4 through 24, but the difference was not significant at any time point.
• EQ-5D-5L Dimensions and Overall Health Utility Score: The mean EQ-5D-5L index values were similar for the placebo and tanezumab 20 mg treatment groups at all time points evaluated.
• Opioid Consumption and Rescue Medication Use: At Week 8, the percent change from Baseline for average daily opioid consumption (ATC and rescue medication in mg of morphine equivalent dose) was numerically similar between the tanezumab 20 mg and placebo treatment groups and not significant (p=0.8692). The mean average daily number of doses of rescue medication was significantly lower for the tanezumab 20 mg treatment group compared with placebo at Week 4 (p=0.0211) and numerically lower for the tanezumab 20 mg treatment group than the placebo treatment group at Weeks 1, 2, 6, 8, 12, 16, and 24, although analysis showed no significant differences between treatment groups (all p-values ≥0.0750).
• Opioid-Related Symptom Distress Scale: There were no significant differences in the change from Baseline in the frequency, severity, distress, or multi-domain average composite scores between the tanezumab 20 mg and placebo treatment groups at any week.Pharmacokinetic and Pharmacodynamic Results:
Pharmacokinetic Results:
At Weeks 8 and 24, the mean tanezumab plasma concentrations were higher in the tanezumab 20 mg treatment group than the tanezumab 10 mg treatment group by a proportion approximately similar to the higher dose. By Week 48, 32 weeks after the third dose of study medication, the mean tanezumab plasma concentrations were low, consistent with complete elimination of tanezumab from the body over five half-lives post-injection and were similar for the two treatment groups.Pharmacodynamic Results:
Mean and median soluble p75 serum trough concentrations were comparable at all time points for all treatment groups. Mean total NGF concentrations were comparable at Baseline across treatment groups. At Week 8, mean total NGF concentrations were higher in the tanezumab 20 mg treatment group than in the tanezumab 10 mg treatment group. Mean proNGF was comparable across treatment groups at all nominal sampling times.Safety Results:
All adverse events described in this report were treatment emergent (TE), unless otherwise specified.A higher proportion of subjects in the tanezumab 20 mg treatment group reported adverse events up to the end of the study compared with the placebo treatment group. The incidence of SAEs or severe adverse events during this period were higher in the tanezumab 20 mg treatment group compared with the placebo treatment group (Table S4). The incidence of treatment discontinuation due to an adverse event during this period was similar between the tanezumab 20 mg (4 subjects [5.6%]) and placebo (5 subjects [6.8%]) treatment groups.
The incidence of adverse events reported during the Treatment Period was similar in the tanezumab 20 mg and placebo treatment groups. The incidence of SAEs or severe adverse events during the Treatment Period were higher in the tanezumab 20 mg treatment group compared with the placebo treatment group. The incidence of treatment discontinuation due to an adverse event during the Treatment Period was similar between the tanezumab 20 mg (4 subjects [5.6%]) and placebo (5 subjects [6.8%]) treatment groups.
The most common adverse events occurring in the tanezumab 20 mg were Anemia, Arthralgia, Decreased appetite, Prostate cancer (verbatim term: Progression of prostate cancer), Peripheral edema, and Pain. The proportion of subjects reporting Peripheral edema was higher in the tanezumab 20 mg treatment group compared with the placebo group, as seen in previous tanezumab studies.
• The majority of adverse events reported during the Treatment Period were moderate to severe in severity in both the tanezumab 20 mg and placebo treatment groups.
• The overall incidence of treatment-related adverse events reported during this period was similar across the placebo and tanezumab 20 mg treatment groups in the placebo treatment group.
• The majority of treatment-related adverse events were mild in severity. The General Disorders and Administration Site Conditions system organ class (SOC) had the highest incidence of adverse events in the tanezumab 20 mg treatment group. The Gastrointestinal Disorders SOC and Skin and Subcutaneous Tissue Disorders SOC each had the highest incidence of adverse events in the placebo treatment group.
Up to the end of the study, the placebo treatment group had a larger proportion of subjects who discontinued from treatment and/or the study due to an adverse event (14 subjects [19.2%]) than the tanezumab 20 mg treatment group (11 subjects [15.3%]).
• Adverse events resulting in discontinuation from treatment and/or the study occurred most frequently in the Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) SOC.
• The incidence of discontinuations from treatment and/or the study due to adverse events in the Neoplasms Benign, Malignant and Unspecified (Including Cysts And Polyps) SOC was higher in the placebo group (9 subjects [12.3%]) compared with the tanezumab 20 mg treatment group (6 subjects [8.3%]).
• Most adverse events resulting in discontinuation from treatment and/or the study were moderate to severe in severity.
Throughout the duration of the entire study, 2 subjects temporarily discontinued treatment due to an adverse event and both subjects were in the tanezumab 20 mg treatment group (2 subjects [2.8%]). The causality for both the adverse events was reported as "Not Related; Other Disease Under Study" and they were severe in severity.• Deaths: A total of 46 subjects died during the study. The cause of the death for the majority of subjects across the treatment groups was Neoplasm progression. None of the deaths were considered by the Investigator to be related to study treatment.
• Serious Adverse Events: The incidence of SAEs up to end of study was higher in the tanezumab 20 mg treatment group (39 subjects [54.2%]) compared with the placebo treatment group (28 subjects [38.4%]). The majority of SAEs were in the Neoplasms Benign, Malignant and Unspecified (Including Cysts And Polyps) SOC. Prostate cancer (verbatim term: Progression of prostate cancer) was the most frequently reported SAE in the tanezumab 20 mg and placebo treatment groups. The majority of all reported SAEs were considered by the Investigator to be unrelated to study treatment.
• Adverse Events Related to COVID-19: No treatment-emergent COVID-19-related adverse events were reported. Across the treatment groups, 30 subjects were evaluable for adverse events in the time periods before and during the COVID-19 pandemic. The incidence of adverse events in the during-COVID-19 period was higher than in the period before COVID-19.
• Peripheral Nervous System Adverse Events of Special Interest: Adverse events of abnormal peripheral sensation were reported by 7 subjects (9.7%) in the tanezumab 20 mg treatment group and 4 subjects (5.5%) in the placebo treatment group. In tanezumab 20 mg treatment group, Paresthesia was most frequent (n=2; 2.8%) and the other adverse events were each reported in a single subject. All adverse events of abnormal peripheral sensation during the Treatment Period were mild to moderate in severity. Of the 6 subjects who met criteria for neurological consults, in the tanezumab 20 group, mononeuropathy and radiculopathy were each diagnosed by the blinded external neurologist in 1 subject and no subjects were diagnosed with polyneuropathy; in the placebo group 1 subject was diagnosed with a polyneuropathy.
• Adverse Events Potentially Indicative of Decreased Sympathetic Function: The proportion of subjects reporting adverse events potentially indicative of decreased sympathetic function during the Treatment Period was similar for the tanezumab 20 mg (12 subjects [16.7%]) and placebo treatment groups (9 subjects [12.3%]). The majority of these events in both tanezumab 20 mg and placebo treatment groups was due to nausea and vomiting which are sensitive but not specific for decreased sympathetic function.
• Orthostatic Hypotension: Two subjects had confirmed orthostatic hypotension (OH) during the Treatment Period, 1 subject each in the tanezumab 10 mg and tanezumab 20 mg treatment groups. No subjects in the tanezumab 10 mg or tanezumab 20 mg treatment groups had confirmed OH during the Safety Follow-up Period and no subjects in the placebo or tanezumab 10/20 mg treatment groups had a confirmed OH during the Treatment Period or Safety Follow-up Period based on the protocol specified criteria.
• Sympathetic Function Consultations: The only key adverse events meeting criteria for consultation were Bradycardia in the placebo treatment group and Syncope in the tanezumab 20 mg treatment group, and each occurred with similar frequency (1 subject each). No subject was reported to have Anhidrosis or Hypohidrosis. Sympathetic neuropathy was not confirmed for either subject as determined by the Investigator after a review of clinical data, including available consultation material. There were no apparent changes from Screening among SAS scores.
• Adjudicated Joint Safety Outcomes: A total of four subjects had five events (1 subject had 2 events) that met criteria for adjudication for the tanezumab 20 mg, tanezumab 10 mg, and placebo treatment groups. These included but were not limited to TJRs and possible or probable joint safety events as identified by the Central Reader. Two subjects in the tanezumab 20 mg and one subject each in the placebo and tanezumab 10 mg treatment groups had joint safety events that required adjudication; none were considered related to study treatment by the Investigators. There were two subjects with a composite joint safety endpoint (both Pathological fractures; left acetabulum and right hip respectively). Both subjects were in the tanezumab 20 mg treatment group. One had an associated TJR of the left hip 2 days after the subject discontinued the study due to them NSAE of pathologic fracture of left acetabulum (Pathological fracture of the left acetabulum). Both Pathological fractures occurred at a site of pre-existing bone metastasis and the subject with the fracture of the left acetabulum had received prior radiotherapy of the left hemipelvis. The subject who had TJR of the left hip had no evidence of osteoarthritis (OA) at Screening (Baseline Kellgren-Lawrence grade 0). No subject in any treatment group had a joint safety event adjudicated as Rapidly progressive OA, Primary osteonecrosis, or Subchondral insufficiency fracture. One subject each in the tanezumab 20 mg, tanezumab 10 mg, and in the placebo treatment groups, had joint safety events adjudicated as Other Joint Outcome: normal joint in the tanezumab 20 mg treatment group, extra-articular pathologic fracture in tanezumab 10 mg group, and traumatic avulsion fracture of the ankle in the placebo treatment group. The subject who had a normal joint in the right hip also had a pathological fracture at the left hip and it is described in the preceding paragraph.
• Non-Adjudicated Fractures: Lumbar spinal compression fracture at the site of preexisting bone metastasis was reported in each of 2 subjects in the placebo treatment group. In addition, an extra-articular pathologic fracture of the left femur was reported in one subject in the tanezumab 20 mg treatment group and was considered not related to study medication but rather due to the disease under study.• Total Joint Replacements: One subject in the tanezumab 20 mg group with a reported pathologic fracture of the left acetabulum on Study Day 31 had a TJR of the left hip 2 days after the subject discontinued the study due to the event.
• Clinical Laboratory Evaluation: The incidence of subjects with normal Baseline who had post-Baseline laboratory test abnormalities at any point during the study that met the pre-specified threshold for change from Baseline affected no more than eight subjects within a treatment group for any laboratory parameter, and was similar between tanezumab 20 mg and placebo treatment groups.
• Vital Signs: Categorical changes from Baseline to the last Post-Baseline value in sitting systolic and diastolic BP during the Treatment Period (ie, up to Week 24) were generally comparable in the tanezumab 20 mg and placebo treatment groups.
• ECG: None of the subjects had a QTc corrected using Bazett's formula (QTcB) or QTc corrected using Fridericia's formula (QTcF) value ≥500 msec at any point during the study. There was no apparent difference in the mean maximum changes from Baseline in any of the ECG parameters.
• Neurological Examination (NIS): At the last assessment, the conclusion from the neurological examination for over 75% of subjects in the tanezumab 20 mg and the placebo treatment groups was no new or worsened neurological examination abnormality. One subject (1.5%) in tanezumab 20 mg treatment group and no subjects in the tanezumab 10 mg, tanezumab 10/20 mg, or placebo treatment groups had a new or worsened neurological examination abnormality that was considered by the Investigator to be clinically significant at the last assessment.
• Physical Examination: There was no apparent difference in physical examination findings at Screening between the placebo and tanezumab 20 mg treatment groups.
• Immunogenicity: TE ADA status (ie, TE ADA+ or TE ADA-) did not appear to influence the proportion of subjects identified as responders (ie, Reduction of >=30% from Baseline to Week 8 in the daily average pain intensity in the index bone metastasis cancer pain site) in the tanezumab treatment groups. The overall percent incidence of adverse events in the combined TE ADA+ tanezumab treatment group was comparable to the corresponding TE ADA- combined tanezumab treatment group and there was no association between TE ADA+ and potential hypersensitivity reactions.Conclusion(s):
Efficacy
• Tanezumab 20 mg significantly improved cancer pain predominantly due to bone metastasis at Week 8 versus placebo and met the primary objective of the study.
• Treatment with tanezumab 20 mg resulted in significant improvement (reduction) from Baseline to Week 8 in the daily average pain intensity at the index cancer pain site compared with placebo treatment (p=0.0381 at = 0.0478 in a two-sided test).
• Results of secondary efficacy endpoint analyses supported the primary endpoint analysis:
• Treatment with tanezumab 20 mg resulted in significant improvement from Baseline to Weeks 1, 2, 4, and 6 in the daily average pain intensity and to Weeks 2, 4, and 6 in the daily worst pain intensity at the index cancer pain site compared with placebo treatment.
• Treatment with tanezumab 20 mg resulted in significant improvements at Weeks 2, 4, 6, and 8 in the secondary efficacy endpoint of percent reduction from Baseline in daily average pain intensity in the index cancer pain site (at the ≥50% response level). Significant improvements for tanezumab 20 mg at the ≥70% response level were also noted at Weeks 4 and 6.
• Treatment with tanezumab 20 mg resulted in significant improvements at Weeks 4, 6, and 8 in the secondary efficacy endpoint of percent reduction from Baseline in daily worst pain intensity in the index cancer pain site (at the ≥50% response level).
• Treatment with tanezumab 20 mg resulted in numerical improvement at Week 8 in the secondary efficacy endpoints of daily worst pain intensity at the index cancer pain site, weekly average and worst pain intensity at the non-index cancer pain sites, and PGA of Cancer Pain.
• Numerical reduction relative to Baseline in daily average and worst pain intensity at the index cancer pain site, weekly average and worst pain intensity at the non-index cancer pain sites, and PGA of Cancer Pain was maintained for tanezumab 20 mg over the 24-week Treatment Period. The magnitude of the treatment difference for daily average pain intensity at the index cancer pain site from Weeks 12 to 24 and for PGA of Cancer Pain at Weeks 16 and 24 was lower than at Week 8; however, it should be noted that the study was not designed to determine treatment differences after Week 8.
• Treatment with tanezumab 20 mg resulted in significant improvement from Baseline compared to placebo on the BPI-sf assessments of average pain (at Weeks 4 and 8), worst pain (at Weeks 4 and 24), pain interference index (at Week 8), interference with general activity (at Week 8), and interference with sleep interference (at Week 4).
• Treatment with tanezumab 20 mg resulted in no significant difference in opioid consumption and rescue medication use when compared with placebo except the mean average daily number of doses of rescue medication was significantly lower for the tanezumab 20 mg treatment group compared with placebo at Week 4 (p=0.0211). No apparent differences between tanezumab 20 mg and placebo were observed for OR-SDS.Safety
• The safety findings in this study, including the adverse event profile in the tanezumab treatment groups, were generally consistent with those anticipated in subjects with cancer pain predominantly due to bone metastasis and/or the known safety profile of tanezumab. No new safety risks were identified.
• The incidence of adverse events of abnormal peripheral sensation was higher in the tanezumab treatment groups than in the placebo group, consistent with prior studies.
• There was no evidence of an effect of tanezumab on sympathetic nervous system function.
• There was no evidence of an effect of tanezumab on safety related to vital signs, ECG measures, safety labs, or other body systems.
• Adjudicated joint safety outcomes consisted of an intra-articular pathological fracture in 2 subjects (2.8%) in the tanezumab 20 mg treatment group, both of which occurred at a site of pre-existing bone metastasis. No subject in any treatment group had a joint safety event adjudicated as Rapidly Progressive OA, Primary Osteonecrosis, or Subchondral Insufficiency Fracture. Of the 2 subjects with Pathologic fractures in the tanezumab 20 mg treatment group, 1 subject had an associated TJR. The subject who had the TJR in the hip had no radiographic evidence of OA at Screening.
• A total of three subjects, one subject each in the tanezumab 20 mg, tanezumab 10 mg, and in placebo treatment groups, had joint safety events adjudicated as Other Joint Outcome: the outcomes were normal joint in the tanezumab 20 mg treatment group, extra-articular pathologic fracture in the tanezumab 10 mg group, and traumatic avulsion fracture of the ankle in the placebo treatment group.
• Lumbar spinal compression fractures at the site of pre-existing bone metastasis which did not require adjudication committee review were reported in 2 subjects in the placebo group. An extra-articular pathologic fracture of the left femur which also did not require adjudication committee review was reported in one subject in the tanezumab 20 mg treatment group.
• COVID-19 did not appear to have an impact on the safety results of the study. There were no COVID-19-related adverse events, and the COVID-19 pandemic did not appear to impact timely reporting of adverse events or SAEs.Immunogenicity
• The results suggest that the immunogenicity profile of tanezumab was minimal, as the incidence rate of TE ADA+ was low. The immunogenicity results do not provide any evidence that the presence of TE ADA affects the PK, safety, or efficacy profile of tanezumabREC name
East Midlands - Leicester South Research Ethics Committee
REC reference
15/EM/0424
Date of REC Opinion
7 Oct 2015
REC opinion
Further Information Favourable Opinion