To Check Safety of Ayurvedic Oral Cannabis in Breast and Head and Neck Cancer

Study Overview
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Brief Summary
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Phase 1 study to assess the pharmacokinetic availability and safety and tolerability profile of one such ayurvedic preparation which contains 5 mg THC:CBD 1:1 preparation. Other than the PK profile, we will also be studying its effect on gene expression profiling of the breast and head neck oral cavity squamous cell carcinoma tissue.

Detailed Description
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The ancient Ayurvedic medicine obtained from Cannabis sativa plant has recently been re-explored for its anti-inflammatory and anti-cancer potential. Various laboratory and preclinical studies have proven its anti-cancer activity and its effect on all the hallmarks of cancer. Anecdotal clinical evidence has shown regression of tumours with ingestion of such medicinal cannabis. A randomized controlled trial in Glioblastoma Multiforme, a kind of brain tumour, shows improvement in disease free survival when temozolamide was combined with Cannabis spray called Sativex. However, because of lack of systematic, large volume studies, the evidence is slow to emerge. We have previously seen changes related to NF-kb (inflammation) and AP1 (acute hypoxia/stress) pathway genes within the tumour tissue as assessed by transcriptomic analysis (Yet unpublished data). There is laboratory evidence to suggest that the changes induced in the AP1 pathway during surgery can be ameliorated by cannabis treatment. We intend to explore this anticancer potential of C sativa herbal preparation in the pre-operative setting in breast and head and neck cancer patients. Hence, we are proposing a phase 1 study to assess the pharmacokinetic availability and safety and tolerability profile of one such ayurvedic preparation which contains 5 mg THC:CBD 1:1 preparation. Other than the PK profile, we will also be studying its effect on gene expression profiling of the breast and head neck oral cavity squamous cell carcinoma tissue.

Official Title
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Phase I Study of Safety and Feasibility of Ayurvedic Oral Cannabis Preparation in the Peri-operative Period in Breast and Oral Cavity Squamous Cell Cancer

Conditions
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Breast Cancer, Oral Cancer

Intervention / Treatment
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* Drug: Cannabis capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically proven patients of breast or oral cavity SCC Age > 18 and < 65 Operable cancers planned to undergo upfront curative surgery Patient fit for surgery (ASA Grade I / II) Patient Voluntarily willing to give consent for study Exclusion Criteria: Planned for any other pre or peri-operative intervention such as neoadjuvant chemotherapy or targeted therapy or radiation Presence of medical disease such as pulmonary, renal, liver, gastro-intestinal disease which may interfere with any study specific procedure (deranged renal parameters > 1.5 times normal range or deranged liver function tests such as > 2.5 times raised liver enzymes) History of substance abuse (including cannabis-related products) or alcohol abuse Personal history of psychiatric disease or Significant family history of psychiatric disease Pregnancy and/or lactation Patients currently (within last 14 days before consenting) on other CNS depressants such as alcohol, barbiturates, benozodiazapines (like diazepam, alprazolam etc) Patients on other medications which will likely have a drug interaction with cannabis- such as clozapine, duloxetine, naproxen, cyclobenzaprine, olanzapine, haloperidol, and chlorpromazine, macrolides, calcium channel blockers, benzodiazepines, cyclosporine, sildenafil (and other PDE5 inhibitors), antihistamines, haloperidol, antiretrovirals Any other illness or abnormal laboratory investigations which the investigator considers as making the patients ineligible for the study Any patient with positive HIV, HBsAg, HCV status

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: To determine the maximum tolerated dose (MTD). First 3 patients will receive the study preparation once a day at 9 am (+/- 60 min) (i.e 5 mg of CBD and 5 mg of THC in a 400 mg capsule). Subsequent cohorts will be administered doses of 10 (10 mg of THC and CBD each), 20 (20+20) and 30 (30+30) mg in a classical 3+3 dose escalation study. Briefly, 3 patients will be enrolled at dose level. Dose escalation to the next dose level will continue as long no DLT is observed in 3 patients (the incidence of DLT is ≤ 1/6) In any cohort, if 1/3 patients develop DLT, then 3 more patients will be added at that dose. The dose level at which more than 1/6 patients develop DLT will be considered the MTD and no further escalation will be done beyond the MTD. One dose level below the MTD will be considered for future trials. If MTD is not achieved, the highest dose (30+30) will be considered for future trials. If toxicity is seen at 30 mg, then de-escalation to 25 mg may be considered.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabis<br>Cannabis capsules containing 5 mg of THC and CBD each or 2.5 mg of THC and CBD each. | Drug: Cannabis capsules<br>* Cannabis capsules containing 5 mg of THC and CBD each or 2.5 mg of THC and CBD each.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish safe dose of oral cannabis preparation | Number of participants with treatment-related adverse events with respect to cardiovascular, central nervous system and psychotropic of cannabis as assessed by CTCAE v4.0 | From day 1 of IP dosing till 28 days . | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profiling | Blood samples collected during the administration of the IP for 5 days and up to 72 hours after surgery. | 1.Pre operative day 1 to 5 - one each day before cannabinoid dosing, after dosing 30 minutes, 1 hour, 2 hour and 8 hour. 2. On day of surgery - Before and after the surgery 3. Post operative day 1 , day 2, day 3 and day 14 | 
| Biomarker analysis- Transcitpomics | Tumor and normal tissue samples. | A baseline pre-cannabis tumor tissue sample will be collected before starting IP(day 0). Further blood and tumor as well as adjacent normal tissue samples will be collected during surgery (day6). |