Clinical trial NCT03984214: Efficacy and Safety of Dronabinol in the Improvement of Chemotherapy-induced and Tumor-related Symptoms in Advanced Pancreatic Cancer
Official title: Multicenter, Randomized, Double-blind, Placebo-controlled, Phase III Clinical Trial to Investigate the Efficacy and Safety of Dronabinol in the Improvement of ChemOthErapy-induced and Tumor-Related Symptoms in Patients With Locally Advanced or Metastatic Pancreatic Cancer During First-line Chemotherapy (DIsCOvER)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pancreatic Cancer Non-resectable
Chemotherapy-induced Nausea and Vomiting
Pancreatic Cancer Metastatic
Keywords: Dronabinol
THC
Placebo
Pancreatic Cancer
Chemotherapy-induced Nausea and Vomiting
Tumor related symptoms
Quality of life
EORTC QLQ-C30
FOLFIRINOX
Abraxane
Gemcitabine
Lead sponsor: Arbeitsgemeinschaft medikamentoese Tumortherapie
Sponsor class: OTHER
Collaborators: name: Medical University of Graz
name: Unidata Geodesign
name: Bionorica SE
First posted: 2019-06-12
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Aim of this phase III trial is to investigate the efficacy and safety of dronabinol (orally administered tetrahydrocannabinol (THC)) as adjuvant therapy to first-line standard chemotherapy in patients with metastatic pancreatic cancer for improvement of chemotherapy- and tumor-related symptoms applicated by individual titration up to the maximum tolerated dose.

Detailed description: Patients with pancreatic cancer suffer from multiple symptoms related to the tumor itself or induced by the chemotherapy. The available supportive therapy is still not able to relief all symptoms that are caused by the malignancy itself as well as by the antineoplastic therapy.

Additionally, anorexia and weight loss, that often result in increased morbidity and mortality in this patient population as well as in psycho-social burden and suffering in patients and their relatives, are unmet needs in pancreatic cancer patients.

Therapeutic approaches focus on treating the malignancy itself, additional nutritional support and physical examination might prevent patients from further side effects such as sarcopenia.

During the last decades a number of appetite-modulating drugs have been under clinical investigation. A number of studies focused on the endocannabinoid system, which is involved amongst others in appetite-modulating, antiemetic, analgesic and anti-inflammatory processes.

As dronabinol is already used as magistral formulation, its beneficial effect has often been observed in these patients in the clinical routine, especially in patients with therapy-refractory nausea and emesis. Due to its broad efficacy it might be of benefit for patients suffering from malignancy. Thus, investigators want to evaluate the efficacy of dronabinol in the improvement of chemotherapy-induced and tumor-related symptoms in advanced pancreatic patients during systemic first-line chemotherapy. However, data on optimal dosage are conflicting yet.

In detail, investigators want to study whether dronabinol has a positive influence on quality of life and whether symptoms caused by the tumor or by the chemotherapy itself might be palliated by dronabinol. Beneficial and potential harmful side effects and the personal perception of advanced pancreatic cancer patients will be documented.

Eligibility criteria: Inclusion Criteria:

* Male and female subjects aged ≥18
* Patients with diagnosis of locally advanced, inoperable or metastatic pancreatic cancer, eligible for first-line chemotherapy with FOLFIRINOX or gemcitabine+Abraxane®
* According to investigator life expectancy of \> 4 months at screening
* Female patients must either be post-menopausal or surgically sterilized or use a highly effective method of birth control (hormonal contraceptives, intra-uterine devices, or diaphragms with spermicide) for the duration of the study and/or must have a negative pregnancy test (female patients with childbearing potential only)
* Willing and able to provide written informed consent.
* Written informed consent given prior to any trial-related procedure not part of the normal medical practice.

Exclusion Criteria:

* Patients who are members of the staff of the trial center, staff of the sponsor or CRO, the investigator him/herself or close relatives of the investigator.
* Simultaneous participation in another interventional clinical trial, participation in another trial with less than 30 days or five half-lives of the IMP (whatever is longer) to screening, or previous participation in this trial.
* Ineligible for chemotherapy treatment with FOLFIRINOX or gemcitabine+Abraxane®
* Use of dronabinol or cannabis-based medicine with THC as constituent within 6 months before screening. A urine drug test will be performed during screening phase.
* Use of marihuana within the last 4 weeks and unwillingness to abstain for the duration of the study. A urine drug test will be performed during screening phase.
* Currently receiving chemotherapy or anticipated use of chemotherapy due to any condition not related to locally advanced or metastatic pancreatic cancer
* History of or existing cardiac diseases or pathological findings (e.g. chronic insufficiency NYHA III/IV, severe arrhythmia, unstable angina pectoris, myocardial infarction within the past 6 months, significant QT-prolongation etc.), which in the opinion of the investigator might interfere with the safety or tolerability of the study treatment. An ECG has to be done to exclude pathological findings and must not be older than 3 months before screening or if none is available, has to be performed during the screening phase and assessed prior to randomization
* Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly controlled diabetes
* History of or existing relevant CNS and/or psychiatric disorders (e.g. schizophrenia, psychosis, manic and/or depressive disorders, suicidal ideations, etc) which might interfere with the safety or tolerability of the study treatment. Patients with reactive depression are not excluded from participation.
* Known current or past (within the last year prior to screening) alcohol, narcotics or drug abuse
* Pregnancy or breast feeding
* Known allergy to cannabinoids and other constituents of the investigational medicinal product
* Intake of prohibited concomitant medication
* Any other substantial medical condition that in the opinion of the investigator could create undue risk to the subject or could affect adherence with the trial protocol
* Legal incapacity, limited legal capacity or any other condition which makes the subject unable to understand the subject information and informed consent form (ICF)
* Patients unable or unwilling to waive driving motor vehicles or using machines especially during titration period
* Unable or unwilling to comply with the protocol regulations

Primary outcomes:
measure: Standardized area under the curve of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 symptom summary score over the on-treatment period.
timeFrame: Prior to treatment start until end of 16 weeks maintenance treatment
Secondary outcomes:
measure: Standardized area under the curve of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 symptom summary score over the maintenance period
timeFrame: After 4 weeks of treatment until week 16
measure: Change of European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 symptom summary score from baseline to summary score over the maintenance period
timeFrame: From treatment start until week 16
measure: Symptom scales of European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30
timeFrame: At baseline and 2-weekly until end of treatment at week 18
measure: Global quality of life of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30
timeFrame: At baseline and 2-weekly until end of treatment at week 18
measure: Functional scales of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30
timeFrame: At baseline and 2-weekly until end of treatment at week 18
measure: Mean change from baseline of the Glasgow Prognostic Score
timeFrame: At baseline and at end of treatment at week 16
measure: Amount of concomitant medication taken
timeFrame: From baseline until end of treatment at week 18
measure: Mean time to critical weight-loss (5%)
timeFrame: From baseline until end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Lean body mass (LBM)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Total body water (TBW)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Fat mass (FM)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Body cell mass (BCM)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Extracellular mass (EM)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Phase angle (PA)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Resistance (Rz)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean changes from baseline for Bioelectrical Impedance Analysis (BIA) parameter Reactance(Xc)
timeFrame: At baseline and at end of treatment at week 16
measure: Mean change from baseline of muscle strength
timeFrame: At baseline and at end of treatment at week 16
measure: Proportion of patients not adhering to individual baseline chemotherapy regimen
timeFrame: From baseline until end of treatment at week 18
measure: Chemotherapeutic dose intensity over the treatment period of 18 weeks
timeFrame: From baseline until end of treatment at week 18
measure: Frequency and severity of (serious) adverse events (S)AE
timeFrame: From baseline until safety visit at week 22
measure: Incidence of adverse drug reactions (ARs)
timeFrame: From baseline until safety visit at week 22
measure: Progression-free survival (PFS)
timeFrame: From treatment start until the date of first documented progression or death from any cause assessed up to week 22
measure: Overall survival (OS)
timeFrame: From treatment start until death from any cause assessed up to week 22
Other outcomes:
Locations:
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen GmbH, Abteilung für Innere Medizin IV
state: Oberösterreich
city: Klagenfurt
country: Austria
facility: KABEG-Klinikum Klagenfurt am Woerthersee, Abteilung f. Anaesthesie u. Intensivmedizin
city: Leoben
country: Austria
facility: LKH Hochsteiermark - Standort Leoben Abteilung für Innere Medizin und Hämatologie und internistische Onkologie
city: Salzburg
country: Austria
facility: IIIrd Medical Department, Private Medical University Hospital Salzburg
city: St. Veit an der Glan
country: Austria
facility: Krankenhaus d. Barmherzigen Brüder, Abt. f. Innere Medizin
city: Steyr
country: Austria
facility: Pyhrn-Eisenwurzen Klinikum Steyr, Interne Medizin II
city: Vienna
country: Austria
facility: Hanusch Krankenhaus der Wiener Gebietskrankenkasse
city: Zams
country: Austria
facility: KH Zams, Innere Medizin, Internistische Onkologie u. Haematologie
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Abt. f. Gastroenterologie, gastrointestinale Onkologie u. Endokrinologie
city: München
country: Germany
facility: München Klinik Neuperlach
city: Stuttgart
country: Germany
facility: Marienhospital Onkologie, Hämatologie, Palliativmedizin
Study officials:
affiliation: Med. Dept. III, Hematolog and Oncology
name: Felix Keil, Prof.MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Amerongen G, Kanhai K, Baakman AC, Heuberger J, Klaassen E, Beumer TL, Strijers RLM, Killestein J, van Gerven J, Cohen A, Groeneveld GJ. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Delta9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis. Clin Ther. 2018 Sep;40(9):1467-1482. doi: 10.1016/j.clinthera.2017.01.016. Epub 2017 Feb 9.
citation: Davis MP. Cannabinoids for Symptom Management and Cancer Therapy: The Evidence. J Natl Compr Canc Netw. 2016 Jul;14(7):915-22. doi: 10.6004/jnccn.2016.0094.
citation: Cannabis-In-Cachexia-Study-Group; Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006 Jul 20;24(21):3394-400. doi: 10.1200/JCO.2005.05.1847.
citation: Turgeman I, Bar-Sela G. Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications. Isr Med Assoc J. 2017 Feb;19(2):85-88.
citation: Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, Novotny PJ, Christensen B. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol. 2002 Jan 15;20(2):567-73. doi: 10.1200/JCO.2002.20.2.567.