A phase 2a study on the anti-tumoral effect of cannabis oil (THC 10% / CBD 5%) in patients with untreatable advanced hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) has increased dramatically over
the past decades. It appears frequently in patients with chronic liver disease,
both in the presence or absence of cirrhosis. The development of HCC in
cirrhotic liver is a multistep process that involves sustained inflammatory
damage, including hepatocyte necrosis and regeneration, associated with
fibrotic deposition in the liver. Additionally, HCC can also develop in
non-cirrhotic liver. Although the mechanism of hepatocarcinogenesis in
non-cirrhotic livers is not clear yet, important risk factors include
non-alcoholic fatty liver disease (currently metabolic-associated fatty liver
disease). The majority of patients present with hepatocellular carcinoma (HCC)
at an advanced stage of cancer. It has been demonstrated that approximately one
third of patients presenting with HCC were not suitable for any treatment and
were offered best supportive care.

The biological activities attributed to cannabis are mainly been linked to the
cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These
cannabinoids act on their receptors (cannabinoid-binding (CB) receptors). CB1
receptors mediate the behavioral and psychotropic effects of cannabinoids. By
contrast, the cannabinoid receptor type 2 (CB2) is almost exclusively expressed
by tissue of the immune system, including immune cells (lymphocytes and
macrophages) and tissue (spleen, tonsils, lymph nodes). Here, they influence
the release of cytokines and chemokines and migration of immune cells. The most
well-known effect is caused by THC. It is the primary source of the
psychoactive side effects of cannabis. THC is a partial agonist at CB1 and CB2
receptors with preferential binding to CB1. THC has well documented analgesic
and anti-inflammatory benefits in arthritic and inflammatory conditions. It is
20 times more anti-inflammatory than aspirin, and twice as anti-inflammatory as
hydrocortisone. CBD has much lower affinity for CB1 and CB2 receptors as
compared to THC and it acts as a noncompetitive CB1 and CB2 receptor
antagonist. This activity underlies its neutralizing actions on THC side
effects such as anxiety, tachycardia, and sedation.

Anti-tumor effects of cannabinoids have also been described; results emerging
from preclinical studies suggest that both THC and CBD elicit effects at
different levels of cancer progression, including inhibition of proliferation,
neovascularization, invasion and chemoresistance, induction of apoptosis and
autophagy as well as enhancement of tumour immune surveillance. In case of
hepatocellular carcinoma, THC has been demonstrated to reduce tumor growth both
in vitro and in vivo via apoptosis induction. Interestingly, it appears that
cannabinoid receptors have opposite roles. CB1 agonism appears to drive
hepatocarcinogenesis through increased hepatocyte proliferation and liver
fibrosis, where CB2 receptor reduce HCC formation and outgrowth by an
anti-tumor immune response and induction of apoptosis.
Despite these preclinical results, clinical studies on the anti-tumor effect of
cannabinoids are still lacking. Instead, many oncologic patient use cannabis
oil for pain relief, reduction of chemotherapy-induced nausea and vomiting or
appetite stimulation. It seems that many patients use cannabis oil without
supervision, since cannabis oil can be bought on line. However, the exact
concentrations of cannabinoids in the oils are unclear.

Recently, two of our patients demonstrated complete HCC tumor remission after
being diagnosed (histologically proven) as untreatable. The first used cannabis
oil (THC/CBD) every day. One year later, tumor size reduction was established
by MR imaging. In 2017, total remission was observed after continuing cannabis
oil. Until now, no recurrence has been diagnosed (last MRI 20-5-2020). A second
patient was recently discovered with untreatable HCC who used cannabis oil
(THC/CBD) after his initital diagnosis. He demonstrated reduction in tumor size
and tumor markers during his follow up at the outpatient clinic. His last
imaging did not demonstrate any active tumor tissue, but only rest necrosis.
(last CT 23-9-2020).

This study has been transitioned to CTIS with ID 2024-514049-13-01 check the CTIS register for the current data.

to study the anti-tumor effect of cannabis oil (THC10% / CBD5%) in untreatable
advanced HCC patients based on imaging using RECIST and modified RECIST
(mRECIST) criteria

This study will be a phase 2a study comprising 20 untreatable advanced HCC
patients: 10 cirrhotic HCC patients (Child-Pugh A) and 10 non-cirrhotic HCC
patients. Non-cirrhosis will be defined as normal livers and livers with stage
F1 or F2 fibrosis based on METAVIR score

In case a patient has no exclusion criteria and when informed consent has been
signed, an ultrasound- or CT guided biopsy will be performed for histological
assessment of the tumor. If histology confirms HCC, patients will be included
in the study and baseline parameters will be assessed. These include:
- Abdominal and thoracic CT (if not yet performed)
- blood analysis (37mL in total) for
o liver and kidney function, hematology, chemical blood profile
o tumormarkers (AFP and DCP)
o THC and CBD metabolites
o immune cells including T-cells
- Quality of life questionnaires

The presence of cirrhosis (or grading of fibrosis) will be determined on
histology. In case insufficient liver tissue is present in the biopsy, presence
of fibrosis or cirrhosis will be determined on imaging.

After inclusion, patients will be supplied with cannabis oil (Transvamix oil
(THC10% / CBD5%)) provided by Felix Farma, distributed by the Transvaal
Pharmacy. Every person reacts differently to cannabinoids due to a variety of
reasons including different body compositions, liver function and underlying
cannabinoid tone. Patients will be provided a titration scheme and
self-titrate to their optimal daily dose. Optimal daily dose will be the
maximum daily dose which does not produce adverse events. During the drug
titration period (see chapter 6.6), we will have contact by telephone with
patients every 2-3 days to determine the effective dose. After this, they will
continue using this dose throughout the study. Patients will keep a daily log
in which they note the dose (amount of droplets). Patients are free to skip a
dose or reduce a dose because of side effects, they will note the reason for
this in their daily log as well. The side effects are categorized as follows
[in Dutch]:

1. Feeling high (a cheerful mood that slowly turns into a satisfied feeling of
calm and tranquility)
2. Lethargy
3. Hunger
4. More intense experience of colors and /or sounds
5. Loss of sense of time and /or place
6. Gloomy and/or anxious mood
7. Restlessness and/or insomnia
8. Delusions
9. Increased heartrate
10. Dizziness
11. Hot or cold feeling in the hands and feet
12. Red burning eyes
13. Muscle relaxation
14. Dry mouth
15. Otherwise, namely*..

Every 3 months, tumor parameter assessment will be performed using:
- Abdominal and thoracic CT
- blood analysis (37mL in total) for
o liver and kidney function, hematology, chemical blood profile
o tumormarkers (AFP and DCP)
o THC and CBD metabolites
o immune cells including T-cells
- Quality of life questionnaires

At 6 months after starting cannabis oil, tumor biopsy will be repeated.

Medical cannabis oil: Transvamix oil containing 10% tetrahydrocannabinol (THC)
and 5% cannabidiol (CBD).

Patients who will participate should fullfill a titration period to determine
the optimal daily dose of medicinal cannabis oil. For this, they will have
contact every 2-3 days with a research nurse. After this they will use a daily
log to note daily doses. Uing cannabis oil, patients are not allowed to drive a
car until 2 weeks after the titration period (max. 7 weeks). Patients will
visit the hospital three times for imaging purposes and outpatient clinic
visits, including blood examination. Additionally, they will fill in quality
of life questionnaires 3 times.
A possible benefit by anti-tumor effect is the subject of the study. Since HCC
arising from cirrhotic livers may be different when arising from non-cirrhotic
livers, both groups of patients will participate in this study.
The risk for this study is estimated to be low, according to the NFU risk
classification. Of note, many oncological patients use cannabis oil without
supervision.