Efficacy and Safety of Cannabidiol Oral Solution for Aromatase Inhibitor-Induced Musculoskeletal Pain in Early Hormone-Receptor Positive Breast Cancer

Trial ID: 2023-505380-36-01
Protocol: CSET 2021/3373
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Breast cancer Hormone receptor positive breast cancer

Objectives

The primary objective of this study is to compare the effect of **cannabidiol (CBD)**-oral solution versus placebo on musculoskeletal symptoms associated with adjuvant aromatase inhibitor (AI) therapy in patients with early-stage hormone-receptor positive breast cancer. This is measured using the Brief Pain Inventory Short Form (BPI-SF). The clinical relevance of this objective lies in addressing AI-related musculoskeletal pain, which is a common side effect that can significantly impact the quality of life and adherence to cancer treatment.

Secondary objectives include evaluating the efficacy of CBD-oral solution over 12 weeks on various parameters such as worst pain, pain interference with daily activities, and functioning, stiffness, and pain of the knee and hips. Additionally, the study aims to assess the impact on global and cancer-specific aspects of the patient's quality of life, anxiety, depression, and adherence to AI therapy. The study also seeks to determine the effect on pain medications used for musculoskeletal symptoms. Safety assessments will be conducted to evaluate short-term and long-term safety, including potential side effects such as nausea, gastrointestinal symptoms, cognitive dysfunction, and psychiatric disorders, as well as the risk of drug addiction. Furthermore, the study will explore the psychological profile of patients regarding risk perception and attitude in risk-taking situations. Lastly, the study will investigate potential drug-drug interactions between AIs and CBD-oral solution, given that CBD is a CYP3A4 inhibitor, which may affect AI availability.

Participants

The clinical trial involves a study population comprising **patients** with stage I, II, or III hormone-receptor positive breast cancer who are receiving adjuvant aromatase inhibitors and experiencing AI-related musculoskeletal pain. The trial includes both male and female participants, with an age range of 18 years and older. The participants are required to have a reported average joint pain score of 4 or higher on the Brief Pain Inventory. The selection criteria for the trial population include histologically confirmed invasive breast cancer, positive estrogen and/or progesterone receptor status, and a standard dose of one of the three approved aromatase inhibitors for a specified duration. Participants must have completed any indicated adjuvant or neoadjuvant chemotherapy and radiotherapy according to institutional guidelines. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The study population is characterized by a requirement for adequate bone marrow and organ function, as well as compliance with specific laboratory and ECG parameters. Participants are expected to adhere to highly effective contraception methods if of childbearing potential. The trial includes a vulnerable population, and participants must be affiliated with a social security system or its equivalent. The sponsor has not provided the total number of participants involved in the study.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, 2x2 crossover study** to evaluate the efficacy and safety of cannabidiol (CBD) oral solution in managing joint pain associated with adjuvant endocrine therapy in patients with early-stage hormone-receptor positive breast cancer. The trial will span approximately three years, with an estimated end date of January 1, 2027. Participants will be involved in the study for a maximum treatment period of 12 weeks, during which they will receive either the CBD oral solution or a placebo, with a crossover to the alternate treatment after the initial period.

The study will commence with an inclusion (screening) visit, where eligibility criteria will be assessed, including a confirmed diagnosis of stage I, II, or III breast cancer, ongoing treatment with aromatase inhibitors, and a reported average joint pain score of 4 or higher on the Brief Pain Inventory. Participants must also meet specific laboratory and health criteria, such as adequate bone marrow and organ function, and women of childbearing potential must adhere to strict contraceptive measures.

Following the screening, participants will be randomized to receive either the CBD oral solution or placebo. The primary endpoint is the efficacy of CBD on aromatase inhibitor-associated pain, measured by the Brief Pain Inventory Short Form. Secondary endpoints include assessments of articular function, quality of life, anxiety, depression, adherence to treatment, safety, risk-taking behavior, and daily pain medication consumption.

Study visits will occur at baseline, weeks 12, 25, and 37, with assessments including laboratory tests, questionnaires, and safety evaluations. The end-of-study visit will conclude the participant's involvement, with a final assessment of all study parameters. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of CBD in managing joint pain for this patient population.

Treatment

The clinical trial involves the administration of **LGP PURE CBD 200**, an experimental medication formulated as **oral drops**. The active substance in this formulation is **cannabidiol**, a **phytocannabinoid** derived from the cannabis plant. The medication is administered orally, with a maximum daily dose of 20 mg/kg and a total maximum dose of 1680 mg/kg over a treatment period of 12 weeks. The primary objective is to assess the efficacy and safety of cannabidiol in managing musculoskeletal symptoms associated with adjuvant endocrine therapy in patients with early breast cancer. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, a **placebo** is used as a comparator in this randomized, double-blind, placebo-controlled, 2x2 crossover study. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding is maintained. The placebo will be administered following the same dosing schedule as the experimental treatment, allowing for a direct comparison of outcomes between the cannabidiol and placebo groups. Compliance with the placebo administration will also be monitored to ensure the integrity of the study results.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the impact of cannabidiol (CBD) oral solution on musculoskeletal symptoms associated with adjuvant endocrine therapy in patients with early breast cancer. The primary endpoint is the efficacy of CBD on aromatase inhibitor (AI)-associated pain, which will be measured using the Brief Pain Inventory Short Form (BPI-SF). A one-point difference in the BPI average joint pain score is considered a minimal important difference and clinically meaningful.

Secondary endpoints include assessments of articular function, stiffness, and pain of knees and hips using the Western Ontario and McMaster Universities Osteoarthritis scale (WOMAC). Quality of life (QoL) domains will be evaluated with the EORTC QLQ-C30 and EORTC QLQ-BR45, along with the fatigue subscale EORTC QLQ-FA12. Anxiety and depression will be measured using the Hospital Anxiety and Depression Scale (HADS). Adherence to treatment will be assessed through AI serum levels and patient self-reporting via the Medication Intake Survey (MIS) at baseline and weeks 12, 25, and 37.

Safety will be monitored by a trained research nurse, focusing on side effects measured by CTCAE V.5, particularly nausea, constipation, cognitive dysfunction, and nervous system and psychiatric side effects. Risk-taking behavior will be evaluated using the DOSPERT scale, and daily pain medication consumption for musculoskeletal symptoms will be recorded in a daily diary by each participant. Drug addiction will be assessed using the CAST questionnaire.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient must understand, sign and date the written informed consent form (ICF) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedure as per protocol.
Patient must be affiliated to a social security system or beneficiary of the same.
Patient is ≥ 18 years-old at the time of study inclusion
Patient has histologically confirmed invasive Stage I, II, III breast cancer.
Patient has breast cancer that is positive for ER and/or PgR (nuclear staining of any intensity ≥ 10%)
Patients should be taking a standard dose of one of the three approved AIs (i.e., anastrozole, exemestane, or letrozole) for at least 21 days, and not more than 36 months before trial registration;
If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to randomization.
If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to randomization.
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Patients should report an average joint pain score of ≥ 4 out of 10 on the Brief Pain Inventory (BPI, Appendix 2) within 7 days before registration.
Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative urine or serum pregnancy test (for β-hCG) within 7 days of randomization.
Women of CBP, defined as all women physiologically capable of becoming pregnant, must be willing to use highly effective methods of contraception. It is recommended that sexually active males use a condom during intercourse and it is strongly advised that they do not father a child in this period (a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via seminal fluid). In all patients, contraception must continue during the trial treatment and for 3 months after stopping it, due to AI treatment. For women, highly effective contraception methods include: a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of bilateral oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment; c. Placement of an intrauterine device (IUD). Notes: - Use of oral (estrogen and progesterone), transdermal, injected or implanted hormonal methods of contraception (as well as hormonal replacement therapy) is not allowed in this trial. - Women are considered of CBP unless: they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago.
Specific inclusion criteria for CBD use: 14. Patient has adequate bone marrow and organ function as defined by the following local laboratory values: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L b. Platelets ≥ 100 × 109/L c. Hemoglobin ≥ 9.0 g/dL d. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula. e. Alanine transaminase (ALT) ≤ 1.5 × Upper Limit Normal (ULN) f. Aspartate transaminase (AST) ≤ 1.5 × ULN g. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert’s Syndrome h. International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to randomization). i. Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements (the local laboratory value should be documented within normal limits after the correction) before randomization: i. Sodium ii. Potassium iii. Phosphorus iv. Magnesium v. Total Calcium 15. Standard 12-lead ECG values defined as the mean of the triplicate ECGs as locally assessed: d. QTcF interval (using Fridericia’s correction) at screening < 450 msec e. Mean resting heart rate 50-90 bpm (determined from the ECG)

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Exclusion Criteria

Patient with distant metastases of breast cancer beyond regional lymph nodes (M1 disease according to AJCC 8th edition).
Patient has not recovered from clinical and laboratory acute toxicities of chemotherapy, radiotherapy and/or surgery (i.e. patient has toxicities attributed to prior anti-neoplastic therapy NCI CTCAE version 5.0 grade ≥1 at day of randomization, excluding alopecia and amenorrhea)
Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before ICF signature. Note: Patients with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to randomization
Patient has previous history of bone fracture or surgery of the affected knees, hands or both within 6 months prior to enrolment or known rheumatologic diseases;
Patient has received opioids analgesics, systemic NSAIDs, topical analgesics, oral, intra-articular or intramuscular corticosteroids for treatment of joint pain or joint stiffness within 28 days prior registration;
Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
Patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment.
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection).
Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigators judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ≤5 years.
Participation in a prior interventional study and received trial treatment with an investigational product (or used an investigational device) within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breastfeed during the trial.
Patient under guardianship or deprived of his liberty by a judicial or administrative decision or under justice protection or under curatorship or unable of giving his consent
Specific exclusion criteria for CBD use: 13. Patient with a known hypersensitivity to CBD or any of the excipients of CBD 14. Previous serious adverse reaction to any cannabinoid product such as cannabinoid related psychosis, panic attack or delirium. 15. Recreational or medicinal cannabis or synthetic cannabinoid-based medications (including Sativex®) within 2 weeks before study entry 16. Patient has previous or active psychological, psychiatric or central nervous system disorders, including epilepsy; schizophrenia or any other psychosis, severe borderline personality, patient with significant suicidal ideation. 17. Patient takes drugs as clobazam, valproate, or levodopa; 18. Patient has previous history of substance abuse or dependance to alchol, opioids, amphetamines, benzodiazepines and other illicit stimulants. 19. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: a. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry b. Documented cardiomyopathy c. Prior history of LVEF <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) which did not recover before study entry d. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting trial treatment) iii. Inability to determine the QTcF interval e. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block) f. Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg