Study Assessing the Efficacy and Safety of cANnabidiol Oral Solution for Joint Pain of Adjuvant enDOcrine theRApy in Patients With Early Breast Cancer

Randomized, Double-blind, Placebo-controlled, 2x2 Cross Over Study Assessing the Efficacy and Safety of cANnabidiol Oral Solution for Joint Pain of Adjuvant enDOcrine theRApy in Patients With Early Breast Cancer

Phase III, single-center, randomized, double-blind, placebo-controlled, 2x2 cross- over study, assessing the efficacy of CBD in patients with early HR+ BC, presenting aromatase inhibitor-related musculoskeletal pain

Inclusion Criteria:

General inclusion criteria:

1. 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.

2. Patient must be affiliated to a social security system or beneficiary of the same.

3. Patient is ≥ 18 years-old at the time of study inclusion

4. Patient has histologically confirmed invasive Stage I, II, III breast cancer.

5. Patient has breast cancer that is positive for ER and/or PgR (nuclear staining of any intensity ≥ 10%)

6. 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; premenopausal patients are eligible if they are receiving AIs and ovarian function suppression (LHRH agonist).

7. If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to randomization.

8. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to randomization.

9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

10. Patients should report an Interference pain score of ≥ 4 out of 10 on the Brief Pain Inventory (BPI, Appendix 2) within 7 days before registration.

11. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.

12. 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 14 days of randomization.

13. 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:

    1. 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;

    2. 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;

    3. 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:

    1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

    2. Platelets ≥ 100 × 109/L

    3. Hemoglobin ≥ 9.0 g/dL

    4. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula.

    5. Alanine transaminase (ALT) ≤ 1.5 × Upper Limit Normal (ULN)

    6. Aspartate transaminase (AST) ≤ 1.5 × ULN

    7. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert's Syndrome

    8. 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).

    9. 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:

       • Sodium
       • Potassium
       • Phosphorus
       • Magnesium
       • Total Calcium

15. Standard 12-lead ECG values defined as the mean of the triplicate ECGs as locally assessed:

    1. QTcF interval (using Fridericia's correction) at screening < 450 msec
    2. Mean resting heart rate 50-90 bpm (determined from the ECG)

Exclusion Criteria:

General exclusion criteria:

1. Patient with distant metastases of breast cancer beyond regional lymph nodes (M1 disease according to AJCC 8th edition).

2. 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)

3. 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

4. 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;

5. 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;

6. Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

7. Patients with moderate (Child-Pugh B) hepatic impairment or severe (Child-Pugh C) hepatic impairment.

8. 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).

9. 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.

10. 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.

11. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breastfeed during the trial.

12. 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 dependence to alcohol, opioids, amphetamines, benzodiazepines and other illicit stimulants.

19. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    1. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry

    2. Documented cardiomyopathy

    3. Prior history of LVEF <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) which did not recover before study entry

    4. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

       • Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
       • 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)
       • Inability to determine the QTcF interval

    5. 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)

    6. Uncontrolled arterial hypertension with systolic blood pressure (SBP) > 160 mmHg