Epidiolex (CBD) in Patients With Biochemically Recurrent Prostate Cancer
The purpose of this phase I/Ib study is to determine the safety profile of Epidiolex (CBD oil) in biochemically recurrent prostate cancer patients. The study consists of a dose escalation part and dose expansion part. The dose expansion part of the study will use the maximum tolerated dose (MTD) determined in the dose escalation part to assess the activity, safety and tolerability of the investigational product in patients with biochemically recurrent prostate cancer after localized therapy with either surgery or radiation.
|Condition or disease||Intervention/treatment||Phase|
|Prostate Cancer Recurrent Prostate Cancer Prostate Adenocarcinoma||Drug: Epidiolex Oral Liquid Product||Phase 1|
Cannabinoids (CBD) have been widely used in medicines for centuries to control pain, nausea or vomiting, and to stimulate appetite, especially in cancer patients. Both cannabinoids receptor 1(CB1) and cannabinoids receptor 2 (CB2) were highly expressed in cultured prostate cancer cells compared to normal prostate cell lines. CBD inhibits tumor growth in xenograft model.
Clinicians have been challenged to improve the treatment of biochemically recurrent (BCR) prostate cancer in which prostatic specific antigen (PSA) rises without radiological or clinical progression years after localized treatment (radical prostatectomy or radiation therapy) with or without hormonal treatment. Approximately 50-90% of men with high-risk prostate cancer will experience a BCR. Based on the abovementioned preclinical observations of CBD’s effect on prostate cancer and its safety data in two non-cancer populations, a phase I study of CBD in men with biochemically recurrent prostate cancer will be conducted.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||21 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/Ib Study on the Safety of Epidiolex in Patients With Prostate Cancer With Rising PSA After Localized Therapy With Either Surgery or Radiation|
|Actual Study Start Date :||August 3, 2020|
|Actual Primary Completion Date :||August 20, 2021|
|Actual Study Completion Date :||August 20, 2021|
A Phase I/Ib on the Safety of Epidiolex in Patients with Prostate Cancer with Rising PSA after Localized Therapy with either Surgery or Radiation
patients with rising PSA after failure of localized therapy will receive Epidiolex PO once daily for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients receive an Epidiolex taper for 7-10 days after withdrawing from study for any reason or completion of the study period.
Number of participants with dose-limiting toxicities (treatment-related adverse events) as assessed by the CTCAE v5.0 [ Time Frame: up to 90 days ]
Treatment-related adverse events are those that comprise a dose-limiting toxicity within 30 days after initiation of Epidiolex (i.e., acute DLT). Additionally, Treatment-related adverse events will continue to be monitored for a total of 90 days.
Change in serial PSA levels from baseline throughout the treatment period as an indication of biochemical response. [ Time Frame: within 90 days ]
Biochemical response will be determined by the measurement of PSA at baseline and approximately every 4 weeks during treatment.
Biochemical response will be determined by measurement of PSA approximately every 4 weeks during treatment. PSA velocity is the change in PSA levels over time.
Biochemical response will be determined by measurement of testosterone level approximately every 4 weeks during treatment.
The EORTC quality of life questionnaire (QLQ) 30 is a validated 30-item patient-reported questionnaire assessing quality of life among cancer populations. The quality of life questionnaire-C30 is the core QOL instrument, with 30 items that comprise five functioning scales (physical, social, role, cognitive, and emotional functioning), eight symptom scales (fatigue, nausea/vomiting, pain, dyspnea, sleep disturbances, appetite loss, constipation, and diarrhea), financial impact, and overall quality of life. All raw item scores are transformed to scale scores, linearly converted to range from 0 to 100. For the functioning scales and global QOL, higher scores indicate better functioning. For the symptom scales, higher scores indicate higher symptom burden.
The EORTC quality of life questionnaire (QLQ)-PR25 is a validated 25-item patient-reported questionnaire which complements the EORTC QLQ-C30,core QOL questionnaire. The QLQ-PR25 comprises 25 items assessing sequelae specific to prostate cancer and its treatment, and thus, is intended to supplement the EORTC QLQ-C30. The 25 items comprise six prostate-specific scales: Urinary, Bowel, Use of Incontinence Aids, Prostate Cancer Treatment-Related Symptoms, Sexual Active and Sexual Function. Raw item scores are linearly transformed to a 0 to 100 scale (i.e., same unit of measurement used by the core QLQ-C30 questionnaire). For the QLQ-PR25, higher scores on symptom domains (e.g., urinary, bowel, etc.) indicate greater symptom burden. Higher scores on function domains (e.g., Sexual Function) indicate better functioning.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||Male|
|Gender Based Eligibility:||Yes|
|Gender Eligibility Description:||prostate cancer only occurs in male|
|Accepts Healthy Volunteers:||No|
- Completion of localized therapy (prostatectomy or radiotherapy) for prostate adenocarcinoma (either histologically or cytologically confirmed)
- Biochemical (PSA) recurrence, defined as: * PSA of >= 0.2 ng/ml that has increased above nadir following radical prostatectomy OR * PSA increase of 2.0 ng/ml above post-therapy nadir after radiotherapy NOTE: PSA measured at two consecutive time points (separated by 4 or more weeks) is required in order to demonstrate the requisite increase in PSA
- Eastern Cooperative Oncology Group (ECOG) performance status = < 2
- Absolute neutrophil count >= 1,500/microliters (at baseline [pre-study])
- Platelets >= 80,000/microliters (at baseline [pre-study])
- Total bilirubin = < institutional upper limit of normal (at baseline [pre-study])
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase) = < institutional upper limit of normal (at baseline [pre-study])
- Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 using the Cockcroft-Gault formula (at baseline [pre-study])
- Patients with a prior or concurrent malignancy (non-prostate) whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by the treating physician are eligible
- Given that worsening of an underlying state of mental depression or suicidal ideation has been reported with Epidiolex, patients should be carefully screened for depression at baseline and if there are indications or a history of depression it is strongly recommended that these patients be closely followed together with behavioral health or psychiatric medical support. Patients with an established diagnosis of depression that, in the assessment of the investigator may make the administration of Epidiolex hazardous, should not be enrolled on this protocol
- Concurrent use of over-the-counter CBD oil, Marinol or marijuana is not permitted. Patients with a history of current over-the-counter CBD oil, Marinol or marijuana use for any reason are eligible only if they do the following: * Complete a one-week washout period prior to study initiation * Refrain from non-study related CBD oil, Marinol or marijuana use while on-study
- Ability to understand and the willingness to sign a written informed consent document
- History of hypersensitivity to Epidiolex (cannabidiol) or sesame seeds (one of the inactive ingredients in Epidiolex)
- Any radiological evidence of metastatic disease (determined by standard of care computed tomography [CT] scans of abdomen. pelvis, chest, whole body bone scan or Axium positron emission tomography scan). Questionable lesions on bone scan will be confirmed by standard of care methods such as plain X-rays or Axium positron emission tomography scan, if not previously performed
- Receipt of prior cytotoxic chemotherapy for recurrent prostate cancer
- Use of androgen deprivation therapy (for example, bicalutamide, flutamide, nilutamide, or leuprolide acetate) concurrently or within the previous 3 months.
- Uncontrolled intercurrent illness such as active infections. Other illnesses will be evaluated and eligibility status determined at the discretion of the treating physician and the investigator
- Psychiatric illness/social situations that would limit compliance with study requirements
- Concomitant use of valproate or clobazam
- Concurrent use of over-the-counter CBD oil, Marinol or marijuana
- Epidiolex is a moderate inhibitor of CYP2C19 and a moderate/strong inhibitor of CYP3A4, therefore concurrent use of CYP2C19 substrates is not allowed
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04428203
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Using cannabis in prostate cancer patients
In our hospital’s daily practice we notice the popular use of cannabis oil in prostate cancer (PCa) patients. As a nursing specialist for urology, I have even met patients who are so convinced of the curative benefits of cannabis oil in treating prostate cancer that they replace standard treatment with the use of cannabis oil.
These patients include those who have localised prostate cancer where active surveillance is followed, those with biochemical recurrence after treatment, and patients with metastatic PCa. I have always wondered whether cannabis oil could indeed be a cure for prostate cancer. Unfortunately, I do not see in practice the desired beneficial effect and the PSA values continue to rise. To find some answers, I did a search in scientific literature.
Cannabis, a very easy plant to grow, has been used for centuries for its medicinal properties. The oldest known document about cannabis use originates from the Chinese emperor Shen Nung in 2727 B.C. It suggested that cannabis has a neuron-protective effect. The Egyptians used cannabis to treat glaucoma and as an anti-inflammatory agent (inflammation of the eyes, fever). Cannabis was even used in obstetrics (mixed with honey) and the mixture was applied in the vagina to “cool” the uterus. In the Old Testament, there is also an account of God instructing Moses to make a holy anointing olive oil-based “Kaneh Bosm.”
Cannabis contains more than 400 chemical components 80 of which contain cannabinoid components and 200 non-cannabinoids components. For medical purposes, cannabinoid substances such as THC (Delta-9-tertrahydrocannabinol), CBD (cannabidiol) and non-cannabinoid substances such as terpenoids and flavonoids are relevant.
Medicinal cannabis must be distinguished from recreational cannabis which is used to achieve a psychotomimetic state of ‘high’. Cannabis strains used for recreational purposes contain a higher THC and lower CBD ratio than cannabis for medicinal use. Usually two cannabis plants are used: cannabis sativa which has a higher THC concentration and cannabis indica which has a higher CBD concentrate. The flavonoids are known for their antioxidant and anti-inflammatory effects. The terpenoids are resins (oil) with a strong odour.
In the 1990s, the endocannabinoid system (ESC) of the body was discovered by Raphael Mechoulam, an Israeli professor of medical chemistry. The endocannabinoid system, a central regulatory system, is the body’s largest receptor system and is important to maintain the homeostasis of the body.
Human beings produce their own cannabinoids (endocannabinoids) according to need and are not stored in the body. Like endorphins, the human body produces endocannabinoids in response to activities such as physical exercise (the high of runners might be due to endocannabinoids, not endorphins!).
Cannabinoid receptor type 1 (CB1) is mainly found in the brain, and also in the lungs, the reproductive organs, etc. Cannabinoid receptor type 2 (CB2) is usually located in the immune system and in the bones. THC mainly works on CB1 receptors, CBD on CB2 receptors.
In vitro studies with THC have shown that cannabinoids affect migration, angiogenesis and apoptosis (programmed cell death) of cancer cells, but each type of cancer appears to respond differently to the effect of exogenous cannabinoids. Many types of cancer cells have a higher concentration of CB1 and CB2 receptors.
Use of cannabis in cancer
– Pain: Cannabinoids have been used for centuries to lessen pain. Historical texts and old pharmacopoeia noted the use of cannabis for menstrual cramps, pain during childbirth, and headaches. Studies have shown that the cannabinoids have no effect on acute pain and post- operative pain. Two placebo-controlled studies with a cannabis extract showed modest benefits when using cannabinoids in addition to opioids and other adjuvant pain-killers in cancer patients with chronic pain. However, the effect of cannabinoids in chronic neuropathic pain was clearly demonstrated in 29 randomized studies.
– Nausea and vomiting: An initial study in 1975 showed a beneficial effect of THC on nausea induced by chemotherapy. Subsequently, two systematic reviews showed benefits of cannabinoids in nausea and vomiting due to chemotherapy, but most studies were observational or uncontrolled.
– Stimulation of appetite: Cannabinoids seem to have only a modest effect in cancer patients with cachexia. More promising results were seen in studies in the population without cancer.
– Pre-clinical studies (in vitro = cells in laboratory and in vivo = in mouse model) have shown the antiproliferative, anti-metastatic, anti-angiogenic and pro-apoptotic effects of cannabinoids in various malignancies (lung, glioma, thyroid, lymphoma, skin, pancreas, endometrium, breast and prostate). Even if an identified substance in vitro / in vivo appears to have a beneficial effect on a disease, it is important to realise that only one in 5,000-500,000 substances obtain a registration and becomes available to the patient (after 10-16 years of different study phases). Cannabis has never been clinically studied as a treatment for malignancy.
On the Internet, patients can get a lot of information about the curative effect of cannabis oil on prostate cancer but this information extrapolate the results of pre-clinical work to possible effects in people without any factual evidence. I often see patients in the doctor’s office showing me a website where it has been proven that cannabis oil can cure prostate cancer, which is obviously their own interpretation. In my view this can be a misleading message even though the website does not explicitly provide false information. The website [See figure below] shows information which is based on a study published in the British Journal of Cancer. This is correct, but the website “neglects” to mention that this is a publication of an in vitro study. The patient might not even know what an in vitro study is and is not aware that there are no studies on humans yet to prove this.
A challenge for the caregiver can be that the patient is convinced that we as healthcare practitioners work together with the pharmacists, and that we do not wish to carry out clinical trials (unfortunately, I hear that very often). We can hardly persuade patients that this is not true.
It is also important that we inform the patient about the possible interactions of cannabis oil with certain regular medications such as Coumarin (this blood thinner interacts with cannabis oil, leading to an increase of the INR and a greater risk of bleeding!). There are different types of cannabis oil available, such as CBD and THC oils with different concentrations which makes it difficult for patients to make a choice.
• There is no proof of cannabis oil as cure for prostate cancer;
• It is important not to be prejudiced or judgmental against patients who use cannabis oil;
• Listening to the patient’s view can be helpful since the patient often confides to the nurse rather than to their physicians;
• Avoid persuading patients not to use cannabis oil, but try to convince them of the need to follow a regular treatment combined with cannabis oil;
• Consider adverse interactions between cannabis oil and certain medications and inform your patient about these.
- Abrams, D.I. Integrating cannabis into clinical cancer care. Current Oncology, 23, S8-S14 (2016).
- Benzi Kluger, Piera Triolo, Wallace Jones, Joseph Jankovic. The Therapeutic Potential of Cannabinoids for Movement Disorders. Mov Disord. 2015 Mar; 30(3):313–327.
- Bowles, D.W, O’Brien, C.L, Camidge D.R, Jimeno A. The intersection between cannabis and cancer in the U.S. Critical Reviews in Oncology/Hematology, 83, 1-10 (2012).
- Bridgeman M.B and Abazia D. T. Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting. P T. 2017 Mar; 42(3): 180–188.
- De Petrocellis L. et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo:pro-apoptotic effects and underlying mechanisms. Br J Pharmacol. 2013 Jan; 168(1): 79–102.
- Guindon, J. Hohmann, A.J. The Endocannabinoid System and Cancer.: Therapeutic Implication. British Journal of Pharmacology. 163, 14447-1463 (2011) – Johnson J.R et al. Multicenter, dubbel blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety and tolerability of THC: CBD extract and THC extract in patients with intractable cancerrelated pain. J.Pain Symptom Manage 2010;39:167-79.
- Machado Rocha F.C. et al. Therapeutic use of Cannabis Sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur. J. Cancer Care 2008;17:431-43.
- Olea-Herrero N. et al. Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2. British Journal of Cancer volume 101, pages 940–950 (15 September 2009).
- Portenoy R.K et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded dose trial. J. Pain 2012;13:438-49.
- Ramos J.A. et al. The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications. Indian J Urol. 2012 Jan-Mar; 28(1): 9–14.
- Tramer M.R. et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16-21.
Corinne Tillier, Nurse Practitioner Urology, Antoni van Leeuwenhoek Hospital, Amsterdam (NL), [email protected]