fentanyl sublingual spray in treating patients with breakthrough cancer pain

Conditions: Cancer

Summary: this is a phase iii, randomized, double-blind, placebo-controlled, multicenter study of the clinical response to fentanyl sublingual spray as a treatment for breakthrough cancer pain. the study medication is administered under the tongue as a simple spray and can be self-administered by patients or assisted by their caregivers. patients are titrated to an effective-dose of fentanyl sublingual spray in the open-label titration period and then proceed to the double-blind randomized period where they randomly receive 7 treatments with fentanyl sublingual spray and 3 treatments with placebo. patients are treated for up to a total of 6-7 weeks (including both the open-label titration and the double-blind randomized periods).

rationale fentanyl sublingual spray may help relieve breakthrough pain in patients receiving opioids for cancer pain. objectives primary * determine the efficacy and safety of fentanyl sublingual spray for the treatment of breakthrough cancer pain in patients on around-the-clock opioids for their persistent cancer pain. secondary * evaluate the safety of fentanyl sublingual spray in these opioid-tolerant patients. * assess the patient's satisfaction with treatment medication.

Eligibility criteria:
inclusion criteria: * male or female, ≥ 18 years of age. * diagnosis of cancer. * opioid-tolerant. subjects who were opioid tolerant were those taking ≥ 60 mg of oral morphine/day, at least 25 μg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer for cancer-related pain. * experienced persistent pain related to the cancer or its treatment of moderate or lesser intensity in the 24 hours prior to assessment by a verbal rating scale at the screening visit. * over the previous 7 days, subject experienced, on average, 1 to 4 breakthrough cancer pain episodes per day usually at least partially controlled by supplemental medication of at least 5 mg immediate-release morphine or an equivalent short-acting opioid (eg, oxycodone, hydrocodone, or codeine with acetaminophen). * able to evaluate and record pain relief, assess medication performance at set times after dosing, record aes, record each use of the study drug or supplemental medication in an electronic diary (a caregiver may have provided the subject the medication, help with the mechanics of handling the electronic diary but was not permitted to record any information in the electronic diary). * able and willing to give informed consent. * women of childbearing potential were to have a) a negative serum pregnancy test, b) not be breastfeeding and c) agree to practice a reliable form of contraception. exclusion criteria: * intolerance to opioids or fentanyl. * current use of commercially available oral short-acting fentanyl for breakthrough pain. subjects previously on actiq or fentora were permitted to be enrolled if they had a 7 day washout. * rapidly increasing/uncontrolled pain. * a history of major organ system impairment or disease, that in the investigator's or his/her designee's opinion could increase the risk associated with the use of opioids. * uncontrolled hypertension (systolic blood pressure {sbp} \> 180 mmhg or diastolic blood pressure \[dbp\] \> 90 mmhg on 2 occasions ≥ 6 hours apart) despite antihypertensive therapy, or a history of hypertensive crisis within the past 2 years. * a recent history (≤ 2 years prior) of transient ischemic attacks, neural vascular disease, stroke, or cerebral aneurysms. * clinically uncontrolled sleep apnea. * brain metastases with signs or symptoms of increased intracranial pressure. * inability to assess pain or response to pain medications for any reason, including psychiatric disorder, concurrent medical disorder, or concomitant therapy. * received investigational study product(s) ≤ 30 days prior to the screening visit. * painful erythema, oedema or ulcers under the tongue. * use of monoamine oxidase (mao) inhibitors within 14 days of the screening visit.

Keywords: unspecified adult solid tumor, protocol specific pain adult acute myeloid leukemia with 11q23 (mll) abnormalities adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) stage iv chronic lymphocytic leukemia accelerated phase chronic myelogenous leukemia blastic phase chronic myelogenous leukemia chronic myelomonocytic leukemia chronic phase chronic myelogenous leukemia noncontiguous stage ii adult burkitt lymphoma noncontiguous stage ii adult diffuse large cell lymphoma noncontiguous stage ii adult diffuse mixed cell lymphoma noncontiguous stage ii adult diffuse small cleaved cell lymphoma noncontiguous stage ii adult immunoblastic large cell lymphoma noncontiguous stage ii adult lymphoblastic lymphoma noncontiguous stage ii small lymphocytic lymphoma noncontiguous stage ii marginal zone lymphoma noncontiguous stage ii grade 1 follicular lymphoma noncontiguous stage ii grade 2 follicular lymphoma noncontiguous stage ii grade 3 follicular lymphoma noncontiguous stage ii mantle cell lymphoma stage iii adult burkitt lymphoma stage iii adult diffuse large cell lymphoma stage iii adult diffuse mixed cell lymphoma stage iii adult diffuse small cleaved cell lymphoma stage iii adult immunoblastic large cell lymphoma stage iii adult lymphoblastic lymphoma stage iii small lymphocytic lymphoma stage iii marginal zone lymphoma stage iii grade 1 follicular lymphoma stage iii grade 2 follicular lymphoma stage iii grade 3 follicular lymphoma stage iii mantle cell lymphoma stage iv adult burkitt lymphoma stage iv adult diffuse large cell lymphoma stage iv adult diffuse mixed cell lymphoma stage iv adult diffuse small cleaved cell lymphoma stage iv adult immunoblastic large cell lymphoma stage iv adult lymphoblastic lymphoma stage iv small lymphocytic lymphoma stage iv marginal zone lymphoma stage iv grade 1 follicular lymphoma stage iv grade 2 follicular lymphoma stage iv grade 3 follicular lymphoma stage iv mantle cell lymphoma recurrent adult burkitt lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult hodgkin lymphoma recurrent adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma recurrent cutaneous t-cell non-hodgkin lymphoma recurrent small lymphocytic lymphoma recurrent marginal zone lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma recurrent mycosis fungoides/sezary syndrome stage i multiple myeloma stage ii multiple myeloma stage iii multiple myeloma de novo myelodysplastic syndromes myelodysplastic/myeloproliferative neoplasm, unclassifiable previously treated myelodysplastic syndromes secondary myelodysplastic syndromes atypical chronic myeloid leukemia, bcr-abl1 negative stage ii adult hodgkin lymphoma stage iii adult hodgkin lymphoma stage iv adult hodgkin lymphoma contiguous stage ii adult burkitt lymphoma stage i adult burkitt lymphoma contiguous stage ii adult diffuse large cell lymphoma contiguous stage ii adult diffuse mixed cell lymphoma contiguous stage ii adult diffuse small cleaved cell lymphoma contiguous stage ii small lymphocytic lymphoma contiguous stage ii marginal zone lymphoma stage i adult diffuse large cell lymphoma stage i adult diffuse mixed cell lymphoma stage i adult diffuse small cleaved cell lymphoma stage i small lymphocytic lymphoma stage i marginal zone lymphoma contiguous stage ii grade 1 follicular lymphoma contiguous stage ii grade 2 follicular lymphoma contiguous stage ii grade 3 follicular lymphoma stage i grade 1 follicular lymphoma stage i grade 2 follicular lymphoma stage i grade 3 follicular lymphoma contiguous stage ii mantle cell lymphoma stage i mantle cell lymphoma contiguous stage ii adult immunoblastic large cell lymphoma stage i adult immunoblastic large cell lymphoma contiguous stage ii adult lymphoblastic lymphoma stage i adult lymphoblastic lymphoma refractory multiple myeloma anaplastic large cell lymphoma angioimmunoblastic t-cell lymphoma recurrent adult t-cell leukemia/lymphoma stage i adult t-cell leukemia/lymphoma stage ii adult t-cell leukemia/lymphoma stage iii adult t-cell leukemia/lymphoma stage iv adult t-cell leukemia/lymphoma stage i cutaneous t-cell non-hodgkin lymphoma stage ii cutaneous t-cell non-hodgkin lymphoma stage iii cutaneous t-cell non-hodgkin lymphoma stage iv cutaneous t-cell non-hodgkin lymphoma stage i mycosis fungoides/sezary syndrome stage ii mycosis fungoides/sezary syndrome stage iii mycosis fungoides/sezary syndrome stage iv mycosis fungoides/sezary syndrome chronic eosinophilic leukemia primary myelofibrosis chronic neutrophilic leukemia essential thrombocythemia polycythemia vera relapsing chronic myelogenous leukemia t-cell large granular lymphocyte leukemia recurrent adult acute lymphoblastic leukemia recurrent adult acute myeloid leukemia untreated adult acute lymphoblastic leukemia untreated adult acute myeloid leukemia secondary acute myeloid leukemia acute undifferentiated leukemia refractory chronic lymphocytic leukemia stage 0 chronic lymphocytic leukemia stage i chronic lymphocytic leukemia stage ii chronic lymphocytic leukemia stage iii chronic lymphocytic leukemia refractory hairy cell leukemia progressive hairy cell leukemia, initial treatment prolymphocytic leukemia recurrent adult grade iii lymphomatoid granulomatosis waldenström macroglobulinemia extranodal marginal zone b-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone b-cell lymphoma splenic marginal zone lymphoma post-transplant lymphoproliferative disorder extramedullary plasmacytoma isolated plasmacytoma of bone monoclonal gammopathy of undetermined significance primary systemic amyloidosis adult acute lymphoblastic leukemia in remission adult acute myeloid leukemia in remission adult grade iii lymphomatoid granulomatosis aids-related peripheral/systemic lymphoma aids-related primary cns lymphoma intraocular lymphoma meningeal chronic myelogenous leukemia primary central nervous system non-hodgkin lymphoma primary central nervous system hodgkin lymphoma stage i adult hodgkin lymphoma recurrent squamous cell carcinoma of the hypopharynx stage i squamous cell carcinoma of the hypopharynx stage ii squamous cell carcinoma of the hypopharynx stage iii squamous cell carcinoma of the hypopharynx stage iv squamous cell carcinoma of the hypopharynx recurrent squamous cell carcinoma of the larynx recurrent verrucous carcinoma of the larynx stage i squamous cell carcinoma of the larynx stage i verrucous carcinoma of the larynx stage ii squamous cell carcinoma of the larynx stage ii verrucous carcinoma of the larynx stage iii squamous cell carcinoma of the larynx stage iii verrucous carcinoma of the larynx stage iv squamous cell carcinoma of the larynx stage iv verrucous carcinoma of the larynx recurrent adenoid cystic carcinoma of the oral cavity recurrent mucoepidermoid carcinoma of the oral cavity recurrent verrucous carcinoma of the oral cavity stage i adenoid cystic carcinoma of the oral cavity stage i mucoepidermoid carcinoma of the oral cavity stage i verrucous carcinoma of the oral cavity stage ii adenoid cystic carcinoma of the oral cavity stage ii mucoepidermoid carcinoma of the oral cavity stage ii verrucous carcinoma of the oral cavity stage iii adenoid cystic carcinoma of the oral cavity stage iii mucoepidermoid carcinoma of the oral cavity stage iii verrucous carcinoma of the oral cavity stage iv adenoid cystic carcinoma of the oral cavity stage iv mucoepidermoid carcinoma of the oral cavity stage iv verrucous carcinoma of the oral cavity stage i squamous cell carcinoma of the lip and oral cavity stage ii squamous cell carcinoma of the lip and oral cavity stage iii squamous cell carcinoma of the lip and oral cavity stage iv squamous cell carcinoma of the lip and oral cavity recurrent basal cell carcinoma of the lip recurrent squamous cell carcinoma of the lip and oral cavity stage i basal cell carcinoma of the lip stage ii basal cell carcinoma of the lip stage iii basal cell carcinoma of the lip stage iv basal cell carcinoma of the lip metastatic squamous neck cancer with occult primary squamous cell carcinoma recurrent metastatic squamous neck cancer with occult primary untreated metastatic squamous neck cancer with occult primary recurrent lymphoepithelioma of the nasopharynx recurrent squamous cell carcinoma of the nasopharynx stage i lymphoepithelioma of the nasopharynx stage i squamous cell carcinoma of the nasopharynx stage ii lymphoepithelioma of the nasopharynx stage ii squamous cell carcinoma of the nasopharynx stage iii lymphoepithelioma of the nasopharynx stage iii squamous cell carcinoma of the nasopharynx stage iv lymphoepithelioma of the nasopharynx stage iv squamous cell carcinoma of the nasopharynx recurrent lymphoepithelioma of the oropharynx recurrent squamous cell carcinoma of the oropharynx stage i lymphoepithelioma of the oropharynx stage i squamous cell carcinoma of the oropharynx stage ii lymphoepithelioma of the oropharynx stage ii squamous cell carcinoma of the oropharynx stage iii lymphoepithelioma of the oropharynx stage iii squamous cell carcinoma of the oropharynx stage iv lymphoepithelioma of the oropharynx stage iv squamous cell carcinoma of the oropharynx recurrent esthesioneuroblastoma of the paranasal sinus and nasal cavity recurrent inverted papilloma of the paranasal sinus and nasal cavity recurrent midline lethal granuloma of the paranasal sinus and nasal cavity recurrent squamous cell carcinoma of the paranasal sinus and nasal cavity stage i esthesioneuroblastoma of the paranasal sinus and nasal cavity stage i inverted papilloma of the paranasal sinus and nasal cavity stage i midline lethal granuloma of the paranasal sinus and nasal cavity stage i squamous cell carcinoma of the paranasal sinus and nasal cavity stage ii esthesioneuroblastoma of the paranasal sinus and nasal cavity stage ii inverted papilloma of the paranasal sinus and nasal cavity stage ii midline lethal granuloma of the paranasal sinus and nasal cavity stage ii squamous cell carcinoma of the paranasal sinus and nasal cavity stage iii esthesioneuroblastoma of the paranasal sinus and nasal cavity stage iii inverted papilloma of the paranasal sinus and nasal cavity stage iii midline lethal granuloma of the paranasal sinus and nasal cavity stage iii squamous cell carcinoma of the paranasal sinus and nasal cavity stage iv esthesioneuroblastoma of the paranasal sinus and nasal cavity stage iv inverted papilloma of the paranasal sinus and nasal cavity stage iv midline lethal granuloma of the paranasal sinus and nasal cavity stage iv squamous cell carcinoma of the paranasal sinus and nasal cavity high-grade salivary gland mucoepidermoid carcinoma low-grade salivary gland mucoepidermoid carcinoma recurrent salivary gland cancer salivary gland acinic cell tumor salivary gland adenocarcinoma salivary gland adenoid cystic carcinoma salivary gland anaplastic carcinoma salivary gland malignant mixed cell type tumor salivary gland poorly differentiated carcinoma salivary gland squamous cell carcinoma stage i salivary gland cancer stage ii salivary gland cancer stage iii salivary gland cancer stage iv salivary gland cancer adult grade i meningioma adult choroid plexus tumor adult craniopharyngioma adult myxopapillary ependymoma adult diffuse astrocytoma adult pilocytic astrocytoma adult pineocytoma adult ependymoma adult subependymoma adult oligodendroglioma adult subependymal giant cell astrocytoma meningeal melanocytoma adult meningeal hemangiopericytoma adult pineal gland astrocytoma adult central nervous system germ cell tumor adult medulloblastoma adult supratentorial primitive neuroectodermal tumor (pnet) adult ependymoblastoma adult anaplastic astrocytoma adult anaplastic ependymoma adult glioblastoma adult gliosarcoma adult giant cell glioblastoma adult grade iii meningioma adult anaplastic oligodendroglioma adult pineoblastoma adult mixed glioma recurrent adult brain tumor adult anaplastic meningioma adult papillary meningioma adult brain stem glioma stage ia cervical cancer stage ib cervical cancer stage iia cervical cancer stage iib cervical cancer stage iii cervical cancer stage iva cervical cancer stage ivb cervical cancer recurrent cervical cancer recurrent endometrial carcinoma stage i endometrial carcinoma stage ii endometrial carcinoma stage iii endometrial carcinoma stage iv endometrial carcinoma fallopian tube cancer recurrent ovarian epithelial cancer recurrent ovarian germ cell tumor stage i ovarian epithelial cancer stage i ovarian germ cell tumor stage ii ovarian epithelial cancer stage ii ovarian germ cell tumor stage iii ovarian epithelial cancer stage iii ovarian germ cell tumor stage iv ovarian epithelial cancer stage iv ovarian germ cell tumor ovarian sarcoma ovarian stromal cancer recurrent uterine sarcoma stage i uterine sarcoma stage ii uterine sarcoma stage iii uterine sarcoma stage iv uterine sarcoma recurrent colon cancer stage i colon cancer stage ii colon cancer stage iii colon cancer stage iv colon cancer recurrent bladder cancer recurrent gallbladder cancer stage i bladder cancer stage ii bladder cancer stage iii bladder cancer stage iv bladder cancer recurrent gastric cancer stage i gastric cancer stage ii gastric cancer stage iii gastric cancer stage iv gastric cancer advanced adult primary liver cancer recurrent small intestine cancer localized transitional cell cancer of the renal pelvis and ureter metastatic transitional cell cancer of the renal pelvis and ureter recurrent renal cell cancer recurrent transitional cell cancer of the renal pelvis and ureter regional transitional cell cancer of the renal pelvis and ureter stage i renal cell cancer stage ii renal cell cancer stage iii renal cell cancer stage iv renal cell cancer distal urethral cancer proximal urethral cancer recurrent urethral cancer urethral cancer associated with invasive bladder cancer stage i adrenocortical carcinoma stage ii adrenocortical carcinoma stage iii adrenocortical carcinoma stage iv adrenocortical carcinoma recurrent adrenocortical carcinoma extragonadal germ cell tumor localized gastrointestinal carcinoid tumor metastatic gastrointestinal carcinoid tumor recurrent gastrointestinal carcinoid tumor regional gastrointestinal carcinoid tumor gastrinoma insulinoma wdha syndrome glucagonoma pancreatic polypeptide tumor somatostatinoma recurrent islet cell carcinoma carcinoma of the appendix localized extrahepatic bile duct cancer recurrent extrahepatic bile duct cancer unresectable extrahepatic bile duct cancer localized gallbladder cancer unresectable gallbladder cancer gastrointestinal stromal tumor localized resectable adult primary liver cancer localized unresectable adult primary liver cancer recurrent adult primary liver cancer stage i pancreatic cancer stage ii pancreatic cancer stage iii pancreatic cancer stage iv pancreatic cancer recurrent pancreatic cancer small intestine adenocarcinoma small intestine leiomyosarcoma small intestine lymphoma stage i non-small cell lung cancer stage ii non-small cell lung cancer stage iiia non-small cell lung cancer stage iiib non-small cell lung cancer stage iv non-small cell lung cancer recurrent non-small cell lung cancer pulmonary carcinoid tumor extensive stage small cell lung cancer limited stage small cell lung cancer recurrent small cell lung cancer liver metastases lung metastases primary peritoneal cavity cancer lung papilloma peripheral primitive neuroectodermal tumor of the kidney clear cell sarcoma of the kidney rhabdoid tumor of the kidney congenital mesoblastic nephroma stage ii breast cancer stage iiia breast cancer stage iiib breast cancer stage iiic breast cancer stage iv breast cancer recurrent breast cancer male breast cancer breast cancer in situ localized osteosarcoma metastatic osteosarcoma recurrent osteosarcoma localized ewing sarcoma/peripheral primitive neuroectodermal tumor metastatic ewing sarcoma/peripheral primitive neuroectodermal tumor recurrent ewing sarcoma/peripheral primitive neuroectodermal tumor chondrosarcoma malignant giant cell tumor of bone desmoid tumor stage i adult soft tissue sarcoma stage ii adult soft tissue sarcoma stage iii adult soft tissue sarcoma stage iv adult soft tissue sarcoma recurrent adult soft tissue sarcoma recurrent thymoma and thymic carcinoma advanced malignant mesothelioma localized malignant mesothelioma recurrent malignant mesothelioma phosphaturic mesenchymal tumor stage i malignant testicular germ cell tumor stage ii malignant testicular germ cell tumor stage iii malignant testicular germ cell tumor recurrent malignant testicular germ cell tumor stage 0 penile cancer stage i penile cancer stage ii penile cancer stage iii penile cancer stage iv penile cancer recurrent penile cancer stage i prostate cancer stage iib prostate cancer stage iia prostate cancer stage iii prostate cancer stage iv prostate cancer recurrent prostate cancer stage 0 vaginal cancer stage i vaginal cancer stage ii vaginal cancer stage iii vaginal cancer stage iva vaginal cancer stage ivb vaginal cancer recurrent vaginal cancer stage 0 vulvar cancer stage i vulvar cancer stage ii vulvar cancer stage iii vulvar cancer stage ivb vulvar cancer recurrent vulvar cancer stage 0 anal cancer stage i anal cancer stage ii anal cancer stage iiia anal cancer stage iiib anal cancer stage iv anal cancer recurrent anal cancer stage 0 rectal cancer stage i rectal cancer stage ii rectal cancer stage iii rectal cancer stage iv rectal cancer recurrent rectal cancer stage 0 esophageal cancer stage i esophageal cancer stage ii esophageal cancer stage iii esophageal cancer stage iv esophageal cancer recurrent esophageal cancer stage i thymoma stage ii thymoma stage iii thymoma stage iva thymoma stage ivb thymoma recurrent melanoma stage 0 melanoma stage ia melanoma stage ib melanoma stage iia melanoma stage iib melanoma stage iic melanoma stage iiia melanoma stage iiib melanoma stage iiic melanoma stage iv melanoma