Fentanyl Sublingual Spray in Treating Patients With Breakthrough Cancer Pain
Condition: Cancer
MeSH terms: Cancer Pain
Intervention: Fentanyl sublingual spray; Placebo
Intervention description: In the open-label titration period of the study, participants started at a dose of 100, 200, or 400 µg and titrated upward to a maximum dose of 1600 µg. Titration was stopped when the dose administered provided adequate analgesia for breakthrough pain without unacceptable side effects or the maximum titration period of 21±5 days was reached. In the double-blind period of the study, participants received fentanyl sublingual spray in doses of 100, 200, 400, 600, 800, 1200, or 1600 µg determined in the open-label titration period of the study.; Matching placebo to fentanyl sublingual spray.
Intervention MeSH terms: Fentanyl
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 130.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
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

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).
    

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.