Abstract
This randomized, double-blind (DB), placebo-controlled, phase 2 study assessed the
efficacy and safety of fulranumab as a pain therapy adjunctive to opioids in terminally
ill cancer patients. Ninety-eight patients were randomized (2:1) to receive one subcutaneous
injection of fulranumab (9 mg) or placebo in the 4-week DB phase. Seventy-one (72%)
patients entered the 48-week open-label extension phase and were administered 9 mg
of fulranumab every 4 weeks. The study failed to demonstrated efficacy at the end
of the DB phase (primary endpoint, mean [SD] change in average cancer-related pain
intensity was −.8 (1.26) for fulranumab and −.7 (1.56) for placebo; P = .592). However, potential benefit is suggested based on secondary endpoints (30%
responder rate [P = .020], Brief Pain Inventory-Short Form [BPI-SF] pain intensity subscale [P = .003], and pain interference subscale [P = .006]). The most commonly reported treatment-emergent adverse events were (fulranumab
vs placebo): asthenia (16% vs 10%), decreased appetite (12% vs 6%), fatigue (10% vs
0%), and malignant neoplasm progression (10% vs 0%). Although no differences were
seen between fulranumab and placebo groups on the primary endpoint, improvements in
BPI-SF pain subscale scores and responder rates support further research of anti-nerve
growth factor therapy in cancer-related pain.
Perspective
Efficacy and safety of fulranumab as adjunctive pain therapy in terminally ill cancer
patients were assessed. Results suggest that anti-NGF agents may prove to be novel
additions in helping to optimize pain relief in cancer patients who fail to respond
adequately to opioids and other common co-analgesics.
Key words
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References
- Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis.Auton Neurosci. 2000; 86: 84-93
- NGF and GDNF differentially regulate TRPV1 expression that contributes to development of inflammatory thermal hyperalgesia.Eur J Neurosci. 2004; 20: 2303-2310
- Opioid complications and side effects.Pain Physician. 2008; 11: S105-S120
- Electronic versus paper diaries: A pilot study of concordance and adherence in head and neck cancer patients receiving radiation therapy.Head Neck Oncol. 2010; 2: 29
- Breast cancer-induced bone remodeling, skeletal pain, and sprouting of sensory nerve fibers.J Pain. 2011; 12: 698-711
- Influence of opioids on immune function in patients with cancer pain: From bench to bedside.Br J Pharmacol. 2017; 175, 14: 2726-2736
- An international survey of cancer pain characteristics and syndromes: IASP Task Force on Cancer Pain. International Association for the Study of Pain.Pain. 1999; 82: 263-274
- Pain assessment: Global use of the Brief Pain Inventory.Ann Acad Med Singapore. 1994; 23: 129-138
- Total neuropathy score: Validation and reliability study.Neurology. 1999; 53: 1660-1664
- Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor.Clin Cancer Res. 2000; 6: 90-95
- Prevalence of undertreatment in cancer pain: A review of published literature.Ann Oncol. 2008; 19: 1985-1991
- Translational medicine: Cancer pain mechanisms and management.Br J Anaesth. 2008; 101: 87-94
- Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways.J Biol Chem. 2001; 276: 17864-17870
- Nerve growth factor overexpression and autocrine loop in breast cancer cells.Oncogene. 2003; 22: 5592-5601
- Studies with pain rating scales.Ann Rheum Dis. 1978; 37: 378-381
- Defining the clinically important difference in pain outcome measures.Pain. 2000; 88: 287-294
- How well is cancer pain treated?.Palliat Med. 2011; 25: 398-401
- The epidemiology of cancer pain.Cancer Invest. 2005; 23: 182-190
- A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone.Cancer Res. 2005; 65: 9426-9435
- Novel class of pain drugs based on antagonism of NGF.Trends Pharmacol Sci. 2006; 27: 85-91
- Blocking the effects of NGF as a route to safe and effective pain relief: Fact or fancy?.Pain. 2011; 152: 2200-2201
- Cancer pain management.Minn Med. 2001; 84: 36-39
- Assessing the clinical significance of change scores recorded on subjective outcome measures.J Manipulative Physiol Ther. 2004; 27: 26-35
- Comparative study of electronic vs. paper VAS ratings: A randomized, crossover trial using healthy volunteers.Pain. 2002; 99: 341-347
- Electronic diaries for monitoring chronic pain: 1-year validation study.Pain. 2001; 91: 277-285
- Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain.J Neurosci. 2010; 30: 14649-14656
- Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture.Pain. 2007; 133: 183-196
- Efficacy and safety of tanezumab in the treatment of chronic low back pain.Pain. 2011; 152: 2248-2258
- Neurotrophins and neuropathic pain: Role in pathobiology.Molecules. 2015; 20: 10657-10688
- Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain.Pain. 2013; 154: 1009-1021
- A systematic review of randomized trials on the effectiveness of opioids for cancer pain.Pain Physician. 2012; 15: ES39-ES58
- Summary version of the standards, options and recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002).Br J Cancer. 2003; 89: S67-S72
- Efficacy and safety of oral tapentadol extended release for the management of moderate to severe, chronic malignant tumor-related pain.in: Poster Presented at American Society of Regional Anesthesia and Pain Medicine (ASRA) 11th Annual Pain Medicine Meeting, Miami, FL2012
- Utilization of brief pain inventory as an assessment tool for pain in patients with cancer: A focused review.Indian J Palliat Care. 2011; 17: 108-115
- NGF: The TrkA to successful pain treatment.J Pain Res. 2012; 5: 279-287
- Tanezumab for the treatment of pain from osteoarthritis of the knee.N Engl J Med. 2010; 363: 1521-1531
- Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain.Neuroscience. 2010; 171: 588-598
- Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain.Pain. 2010; 149: 386-392
- Management of opioid side effects in cancer-related and chronic noncancer pain: A systematic review.J Pain. 2003; 4: 231-256
- Value of the Palliative Performance Scale in the prognostication of advanced cancer patients in a tertiary care setting.J Palliat Med. 2013; 16: 887-893
- Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines.Proc Natl Acad Sci U S A. 1998; 95: 5366-5371
- Current aproach to cancer pain management: Availability and implications of different treatment options.Ther Clin Risk Manag. 2007; 3: 381-400
- Nerve growth factor stimulates clonal growth of human lung cancer cell lines and a human glioblastoma cell line expressing high-affinity nerve growth factor binding sites involving tyrosine kinase signaling.Cancer Res. 1995; 55: 2212-2219
- Cancer Pain Relief: With a Guide to Opioid Availability.World Health Organization, Geneva1996
- Global Atlas of Palliative Care at the End of life.WPCA (World Palliative Alliance Care), London2014
- A randomized trial of electronic versus paper pain diaries in children: Impact on compliance, accuracy, and acceptability.Pain. 2004; 107: 213-219
- Treatment of cancer pain.Lancet. 2011; 377: 2236-2247
- Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial.J Pain. 2012; 13: 438-449
- Management of cancer pain.Lancet. 1999; 353: 1695-1700
- What is a “clinically meaningful” reduction in pain?.Pain. 2001; 94: 131-132
- Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale.Eur J Pain. 2004; 8: 283-291
- Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain.Pain. 2013; 154: 1910-1919
- Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain.Osteoarthritis Cartilage. 2011; 19: 639-646
- Cancer pain management: Part II. Interventional techniques.Contin Educ Anaesth Crit Care Pain. 2014; 15: 68-72
- When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function.Pain. 1995; 61: 277-284
- Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization.Pain. 2005; 115: 128-141
- Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis.Pain. 2005; 116: 8-16
- Nerve growth factor effects and receptors in cultured human neuroblastoma cell lines.J Neurosci Res. 1982; 8: 375-391
- Efficacy and safety of tanezumab in the treatment of pain from bone metastases.Pain. 2015; 156: 1703-1713
- Update on anorexia and cachexia.Hematol Oncol Clin North Am. 2002; 16: 589-617
- Accuracy of prognosis prediction by PPI in hospice inpatients with cancer: A multi-centre prospective study.BMJ Support Palliat Care. 2015; 5: 399-404
- Adult cancer pain.J Natl Compr Canc Netw. 2010; 8: 1046-1086
- Pain, neuropathic symptoms, and physical and mental well-being in persons with cancer.Cancer Nurs. 2010; 33: 436-444
- Predicting survival in cancer patients: The role of cachexia and hormonal, nutritional and inflammatory markers.J Cachexia Sarcopenia Muscle. 2012; 3: 245-251
- Prevalence of pain in patients with cancer: A systematic review of the past 40 years.Ann Oncol. 2007; 18: 1437-1449
- Clinical survival predictors in patients with advanced cancer.Arch Intern Med. 2000; 160: 861-868
- Clinical evaluation of mild analgesics: The measurement of clinical pain.Br J Clin Pharmacol. 1980; 10: 319S-327S
- Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial.Neurology. 2014; 83: 628-637
- Opioids and cancer: Friend or foe?.Curr Opin Support Palliat Care. 2016; 10: 109-118
- Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance.J Pharmacol Exp Ther. 2007; 322: 282-287
- Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells.Clin Cancer Res. 2001; 7: 105-112
Article info
Publication history
Published online: October 24, 2018
Accepted:
September 28,
2018
Received in revised form:
September 20,
2018
Received:
July 9,
2018
Footnotes
Supported by Janssen Research & Development, LLC, New Jersey. Dr. Neal Slatkin has served as an advisor to Janssen and has received honoraria from Janssen. All other authors are employees of Janssen Research & Development, LLC, a Johnson & Johnson company and hold stocks in the company.
Drs. Neal Slatkin, John Thipphawong, and Steven Wang designed the study; Drs. Naim Zaki, Steven Wang, John Louie, Panna Sanga, Kathleen M. Kelly, and John Thipphawong were responsible for data collection and analysis; and Steven Wang was the project statistician. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, had final approval of the document and made the final decision about where to publish these data. ClinicalTrials.gov identifier: NCT00929188
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© 2018 by the American Pain Society
