WO2019222459A1 - Cannabinoid preparations and therapeutic uses - Google Patents

Abstract

This disclosure provides cannabinoid preparations in which at least 99% by weight of the preparation is cannabidiol (CBD). This disclosure also provides pharmaceutical compositions containing the cannabinoid preparations and methods of using the pharmaceutical compositions in cancer treatment.

Description

C ANNABIN OID PREPARATIONS AND THERAPEUTIC USES

[01] Each reference, patent, and published patent application cited in this disclosure is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[02] This disclosure relates generally to cancer treatment.

DETAILED DESCRIPTION

[03] This disclosure provides cannabinoid preparations in which at least 99% by weight of the preparation is cannabidiol (CBD). This disclosure also provides pharmaceutical compositions containing the cannabinoid preparations and methods of using the pharmaceutical compositions in cancer treatment.

Cannabinoid Preparations

[04] At least 99% by weight of the cannabinoid preparations disclosed herein is CBD ( e.g ., 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99-99.1%, 99-99.2%, 99-99.3%, 99-99.4%, 99-99.5%, 99-99.6%, 99-99.7%, 99-99.8%, 99-99.9%, 99.1-99.2%, 99.1- 99.3%, 99.1-99.4%, 99.1-99.5%, 99.1-99.6%, 99.1-99.7%, 99.1-99.8%, 99.1-99.9%, 99.2- 99.3%, 99.2-99.4%, 99.2-99.5%, 99.2-99.6%, 99.2-99.7%, 99.2-99.8%, 99.2-99.9%, 99.3- 99.4%, 99.3-99.5%, 99.3-99.6%, 99.3-99.7%, 99.3-99.8%, 99.3-99.9%, 99.4-99.5%, 99.4- 99.6%, 99.4-99.7%, 99.4-99.8%, 99.4-99.9%, 99.5-99.6%, 99.5-99.7%, 99.5-99.8%, 99.5- 99.9%, 99.6-99.7%, 99.6-99.8%, 99.6-99.9%, 99.7-99.8%, 99.7-99.9%, 99.8-99.9%).

[05] In some embodiments, the cannabinoid preparation contains one or more other cannabinoids, such as cannabidivarin (CBDV). In some embodiments, the cannabinoid preparation contains CBD and CBDV and does not contain detectable tetrahydrocannabinol (D9- THC), tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromine (CBC), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBD A), or cannabigerolic acid (CBGA).

[06] In some embodiments, the preparation contains CBD, CBDV, and CBDA and does not contain detectable A9-THC, THCV, CBG, CBC, THCA, or CBGA. Such preparations can be used, for example, to make a pharmaceutical composition containing 100 mg/ml CBD, 1 mg/ml CBDV, and 2 mg/ml CBDA.

[07] In some embodiments, the preparation contains CBD, CBDV, CBDA, and CBG and does not contain detectable A9-THC, THCV, CBC, THCA, or CBGA. Such preparations can be used, for example, to make a pharmaceutical composition containing 100 mg/ml CBD, 25 mg/ml CBG, 1 mg/ml CBDV, and 2 mg/ml CBDA.

[08] In some embodiments, the preparation contains CBD, CBG, and CBDV and does not contain detectable CBDA, A9-THC, THCV, CBC, THCA, or CBGA. Such preparations can be used, for example, to make a pharmaceutical composition containing (a) 200 mg/ml CBD, 50 mg/ml CBG, and 1 mg/ml CBDV; (b) 200 mg/ml CBD, 12.5 mg/ml CBG, and 5 mg/ml CBDV; (c) 100 mg/ml CBD, 50 mg/ml CBG, and 5 mg/ml CBDV; or (d) 100 mg/ml CBD, 50 mg/ml CBG, and 1 mg/ml CBDV.

[09] In some embodiments, the preparation contains CBD and CBG and does not contain detectable CBDV, CBDA, A9-THC, THCV, CBC, THCA, or CBGA. Such preparations can be used, for example, to make a pharmaceutical composition containing 100 mg/ml CBD and 25 mg/ml CBG.

[10] In some embodiments, the cannabinoid preparation contains non-cannabinoid

components such as terpenes, flavonoids, glycosides, and alkaloids. In some embodiments, the cannabinoid preparation contains no detectable myrcene, pulegone, isopulegol, borneol, menthol, nerolidol-cis, g-terpenine, nerolidol-trans, linalyl acetate, eugenol, sabinene, p-cymene, terpineol, camphene, fenchone, b-pinene, eucalyptol, a-terpenine, 3-carene, a-pinene, citral-l, citral-2, citronellol, geraniol, ocimene-2, ocimene-l, or terpinolene.

[11] In some embodiments, 99.5-99.8% by weight of the cannabinoid preparation is CBD. In some of these embodiments, 0.2-0.5% by weight of the cannabinoid preparation is a non- cannabinoid component ( e.g ., one or more of a terpene, a flavonoid, a glycoside, or an alkaloid or a combination thereof). In some embodiments, 99.62% by weight of the cannabinoid preparation is CBD and 0.18% by weight of the cannabinoid preparation is CBDV.

[12] A cannabinoid preparation can be obtained from a Cannabis plant (e.g., Cannabis sativa, Cannabis indica, Cannabis ruderalis). In some embodiments, a cannabinoid preparation is obtained from an industrial hemp plant; i.e., a Cannabis plant that contains less than 0.3% (D9- THC) by dry weight. Methods of isolating cannabinoids from industrial hemp, including CBD- rich hemp, are described, for example, in US 2018/0064055, US 2017/0360861, US 2017/0022132, and US 2017/0051231. See also Example 1, below. Alternatively, a cannabinoid preparation can be produced synthetically (see, e.g., US 2010/0298579).

Pharmaceutical Compositions

[13] A cannabinoid preparation as described above can be provided in a pharmaceutical composition in a long- and/or medium-chain fatty acid carrier. Long-chain fatty acids typically have aliphatic tails of 13-21 carbons, or 22 or more carbons. Medium-chain fatty acids typically have aliphatic tails of 6-12 carbons. In some embodiments, the fatty acid carrier is hemp oil. In some embodiments, the fatty acid carrier is a medium-chain triglyceride (MCT) oil obtained, for example, from coconut oil or palm kernel oil.

[14] In some embodiments, the pharmaceutical composition is a liquid. In some

embodiments, the pharmaceutical composition is formulated for topical administration. In some embodiments, the pharmaceutical composition contains 100 mg/ml of the cannabinoid preparation. In some embodiments, the pharmaceutical composition contains 50 mg/ml of the cannabinoid preparation. Other embodiments of the pharmaceutical composition contain 100- 1500 mg/ml or 100-1000 mg/ml of the cannabinoid preparation (e.g., 100 mg/ml, 103 mg/ml, 125 mg/ml, 128 mg/ml, 151 mg/ml, 155 mg/ml, 200 mg/ml, 256 mg/ml, 217.5 mg/ml, 500 mg/ml, 750 mg/ml, 1000 mg/ml). In some embodiments, the cannabinoid preparation is the only active pharmaceutical ingredient in the pharmaceutical composition.

[15] Examples of pharmaceutical compositions include, but are not limited to, compositions that contain: i. 100 mg/ml CBD, 1 mg/ml CBDV, and 2 mg/ml CBDA; ii. 100 mg/ml CBD, 25 mg/ml CBG, 1 mg/ml CBDV, and 2 mg/ml CBDA; iii. 200 mg/ml CBD, 50 mg/ml CBG, and 1 mg/ml CBDV; iv. 200 mg/ml CBD, 12.5 mg/ml CBG, and 5 mg/ml CBDV; v. 100 mg/ml CBD, 50 mg/ml CBG, and 5 mg/ml CBDV; vi. 100 mg/ml CBD, 50 mg/ml CBG, and 1 mg/ml CBDV; or vii. 100 mg/ml CBD and 25 mg/ml CBG. [16] Liquid pharmaceutical compositions can be provided in a glass or plastic bottle or vial, and a dropper can be included for convenient administration. The pharmaceutical compositions can be stored in a cool, dark place or can be refrigerated. Under such conditions, the

pharmaceutical compositions are stable for at least 14 months from the date of production.

Therapeutic Methods

[17] Pharmaceutical compositions described herein can be administered for various purposes, including for the treatment of dermatological disorders ( e.g ., actinic keratosis and atopic dermatitis) and to treat various types of cancer.“Treat” as used herein does not require complete eradication of the disorder, but may include inhibiting the progression of one or more symptoms of the disorder. For example, treatment of cancer may include inhibiting the progression of a cancer, for example, by reducing proliferation of neoplastic or pre-neoplastic cells; destroying neoplastic or pre-neoplastic cells; or inhibiting metastasis or decreasing the size of a tumor. Cancers that can be treated include, but are not limited to, multiple myeloma (including systemic light chain amyloidosis and Waldenstrom’s macroglobulinemia/lymphoplasmocytic lymphoma), myelodysplastic syndromes, myeloproliferative neoplasms, gastrointestinal malignancies (e.g., esophageal, esophagogastric junction, gallbladder, gastric, colon, pancreatic, hepatobiliary, anal, and rectal cancers), leukemias (e.g, acute myeloid, acute myelogenous, chronic myeloid, chronic myelogenous, acute lymphocytic, acute lymphoblastic, chronic lymphocytic, and hairy cell leukemia), Hodgkin lymphoma, non-Hodgkin’s lymphomas (e.g, B-cell lymphoma, hairy cell leukemia, primary cutaneous B-cell lymphoma, and T-cell lymphoma), lung cancer (e.g, small cell and non-small cell lung cancers), basal cell carcinoma, plasmacytoma, breast cancer, bladder cancer, kidney cancer, neuroendocrine tumors, adrenal tumors, bone cancer, soft tissue sarcoma, head and neck cancer, thymoma, thymic carcinoma, cervical cancer, uterine cancers, ovarian cancer (e.g, Fallopian tube and primary peritoneal cancers), vaginal cancer, vulvar cancer, penile cancer, testicular cancer, prostate cancer, melanoma (e.g, cutaneous and uveal melanomas), non melanoma skin cancers (e.g, basal cell skin cancer, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and squamous cell skin cancer), malignant pleural mesothelioma, central nervous system (CNS) cancers (e.g, astrocytoma, oligodendroglioma, anaplastic glioma, glioblastoma, intra-cranial ependymoma, spinal ependymoma, medulloblastoma, CNS lymphoma, spinal cord tumor, meningioma, brain metastases, leptomeningeal metastases, metastatic spine tumors), and occult primary cancers (i.e., cancers of unknown origin).

[18] Pharmaceutical compositions described herein can be administered in conjunction with one or more other cancer therapies such as chemotherapies, immunotherapies, tumor-treating fields (TTF; e.g ., OPTUNE^® system), radiation therapies (XRT), and other therapies (e.g, hormones, autologous bone marrow transplants, stem cell reinfusions).“In conjunction with” includes administration together with, before, or after administration of the one or more other cancer therapies.

[19] Chemotherapies include, but are not limited to, FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan), FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, oxaliplatin), irinotecan (e.g, CAMPTOSAR^@), capecitabine (e.g, XELODA^®), gemcitabine (e.g, GEMZAR^®), paclitaxel (e.g,

ABRAXANE^®), dexamethasone, lenalidomide (e.g, REVLIMID^®), pomalidomide (e.g, POMALYST^®), cyclophosphamide, regorafenib (e.g, STIVARGA^®), erlotinib (e.g,

TARCEVA^®), ixazomib (e.g, NINLARO^®), bevacizumab (e.g, AVASTIN^®), bortezomib (e.g, VELCADE^®, NEOMIB^®), cetuximab (e.g, ERBITUX^®), daratumumab (e.g, DARZALEX^®), elotumumab (e.g, EMPLICITI™), carfilzomib (e.g, KYPROLIS^®), palbociclib (e.g,

IBRANCE^®), fulvestrant (e.g, FASLODEX^®), carboplatin, cisplatin, taxol, nab paclitaxel (e.g, ABRAXANE^®), 5 -fluorouracil, RVD (lenalidomide, bortezomib, dexamethasone),

pomolidamide (e.g, POMALYST^®), temozolomide (e.g, TEMODAR^®), PCV (procarbazine, lomustine, vincristine), methotrexate (e.g, TREXALL^®, RASETVO^®, XATMEP^®), carmustine (e.g, BICNU^®, GLIADEL WAFER^®), etoposide (e.g, ETOPOPHOS^®, TOPOSAR^®), sunitinib (e.g, SUTENT^®), everolimus (e.g, ZORTRESS^®, AFINITOR^®), rituximab (e.g, RITUXAN^®, MABTHERA^®), R-MPV (vincristine, procarbazine, rituximab), cytarabine (e.g, DEPOCYT^®, CYTOSAR-U^®), thiotepa (e.g, TEPADINA^®), busulfan (e.g, BUSULFEX^®, MYLERAN^®), TBC (thiotepa, busulfan, cyclophosphamide), ibrutinib (e.g, IMBREiVICA^®), topotecan (e.g, HYCAMTIN^®), pemetrexed (e.g, ALIMTA^®), vemurafenib (e.g, ZELBORAF^®), cobimetinib (e.g, COTELLIC^®), dabrafenib (e.g, TAFINLAR^®), trametinib (e.g, MEKINIST^®), alectinib (e.g, ALECENSA^®), lapatinib (e.g, TYKERB^®), neratinib (e.g, NERLYNX^®), ceritinib (e.g, ZYKADIA^®), brigatinib (e.g, ALUNBRIG^®), afatinib (e.g, GILOTRIF^®, GIOTRIF^®), gefitinib (e.g, IRES S A^®), osimertinib (e.g, TAGRISSO^®, TAGRIX^®), and crizotinib (e.g, XALKORI^®).

[20] Immunotherapies include, but are not limited to, checkpoint inhibitors, including monoclonal antibodies such as ipilimumab (e.g, YERVOY^®), nivolumab (e.g, OPDIVO^®), pembrolizumab (e.g, KEYTRETDA^®); cytokines; cancer vaccines; and adoptive cell transfer.

[21] The pharmaceutical compositions can be administered orally. In some embodiments, a pharmaceutical composition is simply swallowed. In some embodiments a pharmaceutical composition is administered by placing an aliquot of the composition sublingually to minimize first-pass metabolism by the liver. In some embodiments, the aliquot is held under the tongue for about 60-90 seconds to permit its absorption. Any remaining oil can be swallowed.

Administration can be once or twice daily. Administration can be prior to a meal.

[22] In some embodiments, a pharmaceutical composition comprising a cannabinoid preparation as described above is administered to a patient with a cancer, including any of those cancers listed above. In some embodiments, as described below, a pharmaceutical composition comprising a cannabinoid preparation as described above is administered to a patient with colon cancer, rectal cancer, pancreatic cancer, multiple myeloma, or glioblastoma multiforme in conjunction with an additional therapy appropriate for the particular cancer. In some

embodiments, a patient may be between 18 and 85 years old. a. Colon Cancer, Rectal Cancer

[23] In some embodiments, a pharmaceutical composition is administered to patient with a colon cancer ( e.g ., stage 0, 1, IIA, IIB, IIC, IIIA, MB, IIIC, IV A, IVB, or IVC) or a rectal cancer ( e.g ., stage I, II, III, or IV). In some embodiments, the pharmaceutical composition is one of the compositions described above. In other embodiments, the pharmaceutical composition comprises cannabidiol. In some embodiments, any of these pharmaceutical compositions is administered in conjunction with a chemotherapy regimen. One example of a chemotherapy regimen for colon cancer and for rectal cancer comprises 12 two-day cycles. On day 1 of each cycle, the patient receives intravenous administration of

i. Leucovorin (folinic acid), 360 mg/m2 over 2 hours;

ii. 5-FU (e.g., EFUDEX^®), 400 mg/m2 bolus followed by 2400 mg/m2 over 46 hours; iii. oxaliplatin (e.g, ELOXATIN^®) or irinotecan (e.g, CAMPTOSAR^®), 100 mg/m2; and

iv. bevacizumab (e.g, AVASTIN^®), 5 mg/kg. b. Pancreatic Cancer

[24] In some embodiments, a pharmaceutical composition is administered to patient with a pancreatic cancer (e.g, stage 0, IA, IB, IIA, IIB, III, or IV). In some embodiments, the composition is administered in conjunction with a chemotherapy regimen. One example of a chemotherapy regimen for pancreatic cancer comprises administration of gemcitabine (e.g, GEMZAR^®), 1000 mg/m2 on days 1, 7, and 15 of a 21 -day cycle. c. Multiple Myeloma

[25] In some embodiments, a pharmaceutical composition is administered to patient with a multiple myeloma ( e.g ., stage I, II, or III). In some embodiments, the composition is

administered in conjunction with a chemotherapy regimen. One example of a chemotherapy regimen for multiple myeloma comprises administration of bortezomib (e.g., VELCADE^®), 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21 -day cycle. d. Glioblastoma

[26] In some embodiments, a pharmaceutical composition is administered to patient with a glioblastoma, e.g, a glioblastoma multiforme (stage IV astrocytoma). In some embodiments, the composition is administered in conjunction with a chemotherapy regimen. One example of a chemotherapy regimen for glioblastoma multiforme comprises concurrent radiation therapy (2 Gy per day for a total of 60 Gy) and temozolomide (TMZ; e.g, TEMODAR^®; 75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of

radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). In some embodiments, following maximal safe resection and completion of radiation therapy, the patient receives alternating electric field therapy (TTFields; e.g, OPTUNE^®) as a Category 1 treatment in conjunction with temozolomide.

[27] In some embodiments, a patient receiving treatment for glioblastoma has one or more of the following:

1. histopathologically confirmed glioblastoma (astrocytoma WHO grade IV)

2. negative 0(6)-methylguanine-DNA methyltransferase (MGMT) promoter

methylation status

3. brain MRI confirmation of disease according to RANO (Response Assessment in Neuro-Oncology) criteria

4. completion of standard-of-care temozolomide-based chemoradiation for post

operative treatment of glioblastoma plus two-to-six week“washout” period and stable-to-improved baseline brain MRI

5. Karnofsky Performance Score > 60%

6. an expected survival of at least six months from the day of enrollment

7. does not consume grapefruit in any form

8. has no severe dysfunction of major organs (e.g., bone marrow, liver, kidneys, heart, lungs) and laboratory results from up to 14 days prior to enrollment fall within criteria: a. Hemoglobin > 10 g/dL

b. Leukocytes > 3,000 per mΐ

c. Absolute neutrophil count > 1,500 per mΐ

d. Platelet count > 100,000 per mΐ

e. BUN < 25 mg

f. Serum creatinine within normal institutional limits OR Creatinine clearance > 60 ml/min/l.73 m2 for patients with creatinine levels above institutional normal

g. Total serum bilirubin within normal institutional limits

h. ALT (SGPT) < 2.5 x the institutional upper limit of normal OR AST (SGOT) < 2.5x the institutional upper limit of normal

[28] In some embodiments, a patient receiving treatment for glioblastoma does not have one or more of the following:

1. positive MGMT promoter methylation status

2. prior radiotherapy for glioblastoma within two weeks of treatment

3. prior chemotherapy, immunotherapy, or radiation therapy for other cancers (except for treatment of limited curable skin cancers)

4. currently or recently (in the previous six months) was part of a clinical trial involving any investigational agents

5. receiving any medications or substances that are known substantial inhibitors or inducers of CYP3 A4

6. is positive for HIV or hepatitis

7. has a history of substance abuse within the last two years before treatment

8. currently uses recreational or medicinal cannabis, synthetic cannabinoid-based

medications, or alcohol

9. known history of severe depression or psychiatric disorders, or active suicidal

ideation

10. uncontrolled intercurrent illness.

[29] In some embodiments, the pharmaceutical composition administered in conjunction with any of the additional therapies described above contains 100 mg/ml of the cannabinoid preparation. In some embodiments, a daily dose of 200 mg of the cannabinoid preparation is administered. In some embodiments, a first sublingual dose of 100 mg is administered in the morning, before the first meal of the day, and a second sublingual dose of 100 mg of the cannabinoid preparation is administered before the evening meal. In some embodiments, the pharmaceutical composition is administered throughout the period the patient is receiving the additional therapy. In some embodiments, continued administration of the pharmaceutical composition is recommended once the additional therapy is completed ( e.g ., at a daily dose of 10, 20, 25, 30, 35, 40, or 50 mg/ml of the cannabinoid preparation).

[30] In any of the embodiments described above, plasma concentrations of CBD, its two major metabolites 7-hydroxy-cannabidiol (7-OH-CBD) and 7-carboxy-cannabidiol (7-COOH- CBD), and the minor metabolite 6-hydroxy-cannabidiol (6-OH-CBD) can be measured using methods well known in the art. See , e.g., Ujvary & Hanus, 2016).

[31] Therapeutic levels of various chemotherapeutic drugs (e.g, TMZ and its active metabolite 3-methyl-(triazen-l-yl)imidazole-4-carboxamide (MTIC) in patients being treated for glioblastoma) can be determined using standard methods well known in the art. Progression-free survival (PFS) can be determined by various methods, including laboratory and radiographic testing. In some embodiments, PFS is determined using only radiographic methods.

[32] Those skilled in the art will appreciate that there are numerous variations and

permutations of the above described embodiments that fall within the scope of the appended claims.

Example 1. Extraction and Crystallization of a Cannabinoid Preparation

[33] Hemp cultivars cloned from high CBD-producing mother plants were transplanted into fields and grown under organic conditions without the use of pesticides or herbicides. Hemp was harvested and flash-dried, and a crude extract was obtained using CO2 as the solvent.

[34] The crude extract was dewaxed using a solvent-assisted precipitation and filtration step to provide a refined extract, which was then placed in a stainless steel crystallization tank. After 24- 48 hours, the crystals were washed several times, dried, and ground, resulting in a crystalline cannabinoid preparation in which 99.8% by weight was CBD.

Example 2. Preparation of a Pharmaceutical Composition

[35] The cannabinoid preparation obtained in Example 1 was formulated in hempseed oil and analyzed for plant-based cannabinoids by convergence chromatography. The data collected were compared to data collected for certified reference standards at known concentrations. Table 1.

Max THC (and Max CBD) were calculated values for total cannabinoids after heating, assuming complete decarboxylation of the acid to the neutral form, i.e., the values were calculated based on the weight loss of the acid group during decarboxylation. Max THC = (0.877 x THCA) + THC. ND = None detected above the limits of detection.

[36] The formulation was tested for microbiological contaminants in accordance with the requirements of ISO/IEC 17-25. The results are shown in Table 2.

Table 2.

*Qualitative calculation based on recorded peak areas.

[37] Finally, the terpene profile of the formulation was analyzed by head-space gas chromatography. The data collected were compared to data collected for certified reference standards at known concentrations. These results are shown in Table 3.

Table 3.

Example 3. Clinical Responses

[38] Cancer patients at Southwest Cancer Center voluntarily added the composition prepared according to Example 2 (“BRCX014”) to their standard of care (SOC) treatment protocols. The dosage was 0.5 ml of BRCX014 twice daily for one year.

[39] The responses of patients with solid tumors were measured by PET, MRI, or CT scans and evaluated using the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines published in Eisenhauer et al., 2009. The responses of myeloma patients were measured by free light chain analysis, lambda light chain measurements, or serum protein electrophoresis (SPEP) M spike and were evaluated using the International Myeloma Working Group (IMWG) consensus criteria published in Kumar et al., 2016.

[40] The RECIST criteria for evaluation of target lesions are:

i. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm .

ii. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

iii. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression). iv. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

[41] The RECIST criteria for evaluation of non-target lesions are

i. Complete Response (CR): Disappearance of all non-target lesions and

normalization of tumor marker level. All lymph nodes must be non-pathological in size (<l0mm short axis).

ii. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or

maintenance of tumor marker level above the normal limits.

iii. Progressive Disease (PD): Unequivocal progression of existing non-target lesions.

The appearance of one or more new lesions is also considered progression.

[42] The IMWG consensus criteria are:

i. Complete response: Negative immunofixation on the serum and urine and

disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.

ii. Partial response: >50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by >90% or to <200 mg per 24 h. If the serum and urine M-protein are unmeasurable, a >50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. If serum and urine M- protein are unmeasurable, and serum-free light assay is also unmeasurable, >50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was >30%. In addition to these criteria, if present at baseline, a >50% reduction in the size (SPD) of soft tissue plasmacytomas is also required.

[43] The responses of the patients treated with standard of care chemotherapy plus BRCX014 are shown in Table 4. Comparisons of these responses to the responses of patients who were treated with standard of care chemotherapy but without BRCX014 are shown in Tables 5A-5F.

In the tables,“Category of Response” refers to the accepted RECIST (solid tumors) or IMWG (multiple myeloma) criteria.

Table 5A. Breast cancer with metastases (Stage IV)

*Based on the presence of pleural effusion

Table 5B. Lung Adenocarcinoma (Stage III)

Table 5E. Pancreatic Cancer (Stage III)

Table 5F. Rectal Cancer (Stage III)

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Claims

1. A cannabinoid preparation, wherein at least 99% by weight of the preparation is cannabidiol (CBD), wherein the cannabinoid preparation is free from detectable

tetrahydrocannabivarin (THCV) and tetrahydrocannabinol (THC).

2. The cannabinoid preparation of claim 1 which further comprises cannabidivarin (CBDV).

3. The cannabinoid preparation of claim 2, wherein 99.6 % by weight of the preparation is CBD and 00.18 % by weight of the preparation is CBDV.

4. The cannabinoid preparation of any of claim 1-3 which further comprises 0.2% to 0.5% by weight of a non-cannabinoid component selected from the group consisting of a terpene, a flavonoid, a glycoside, and an alkaloid.

5. A pharmaceutical composition comprising:

the cannabinoid preparation of any of claims 1-4 as the sole active pharmaceutical ingredient; and

a fatty acid carrier.

6. The pharmaceutical composition of claim 5, wherein the cannabinoid preparation is present in the fatty acid carrier at a concentration of 100 mg/ml.

7. The pharmaceutical composition of claim 5 or claim 6, wherein the fatty acid carrier comprises hemp oil.

8. A method of treating cancer, comprising administering to an individual in need thereof an effective amount of the pharmaceutical composition of any of claims 5-7.

9. The method of claim 8, wherein the cancer is selected from the group consisting of a blood cell cancer, a gastrointestinal cancer, a lung cancer, a breast cancer, a basal cell carcinoma, a squamous cell carcinoma, and a central nervous system (CNS) cancer.

10. The method of claim 9, wherein the cancer is a gastrointestinal cancer, wherein the gastrointestinal cancer is selected from the group consisting of a colon cancer, a pancreatic cancer, a liver cancer, a rectal cancer, and a gallbladder cancer.

11. The method of claim 9, wherein the cancer is a blood cell cancer, wherein the blood cell cancer is selected from the group consisting of a multiple myeloma, a leukemia, and a plasmacytoma.

12. The method of claim 11, wherein the blood cell cancer is a leukemia, wherein the leukemia is selected from the group consisting of an acute myelogenous leukemia, a chronic myelogenous leukemia, an acute lymphocytic leukemia, and a chronic lymphocytic leukemia.

13. The method of claim 9, wherein the cancer is a CNS cancer, wherein the CNS cancer is a glioblastoma multiforme.

14. The method of any of claims 8-13, further comprising administering to the individual second cancer therapy.

15. The method of claim 14, wherein the second cancer therapy is selected from the group consisting of a chemotherapy, an immunotherapy, and a radiation therapy.

16. The method of claim 15, wherein the second cancer therapy is a chemotherapy, wherein the chemotherapy is selected from the group consisting of FOLFOX (leucovorin calcium, fluorouracil, oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, irinotecan), FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan, oxaliplatin), capecitabine, gemcitabine, paclitaxel, dexamethasone, lenalidomide, pomalidomide, cyclophosphamide, regorafenib, erlotinib, ixazomib, bevacizumab, bortezimab, cetuximab, daratumumab, elotumumab, carfilzomib, palbociclib, fulvestrant, carboplatin, taxol, nab paclitaxel, 5- fluorouracil, RVD (lenalidomide, bortezomib, and dexamethasone), and pomolidamide.

17. The method of claim 15, wherein the second cancer therapy is a radiation therapy.

18. The method of claim 15, wherein the second cancer therapy is an immunotherapy.

19. A method of treating colon or rectal cancer, comprising administering to an individual in need thereof:

(a) an effective amount of a pharmaceutical composition comprising cannabidiol; and

(b) a second cancer therapy, wherein the second cancer therapy comprises:

(i) leucovorin calcium, fluorouracil, and oxaliplatin;

(ii) leucovorin calcium, fluorouracil, and irinotecan;

(iii) leucovorin calcium, fluorouracil, irinotecan, and oxaliplatin; or

(iv) leucovorin calcium, irinotecan, and oxaliplatin.

20. The method of claim 19, wherein the second cancer therapy further comprises bevacizumab.

21. The method of claim 19, wherein the pharmaceutical composition comprises:

(a) a cannabinoid preparation, wherein at least 99% by weight of the preparation is cannabidiol (CBD), wherein the cannabinoid preparation is free from detectable tetrahydrocannabivarin (THCV) and tetrahydrocannabinol (THC); and

(b) a fatty acid carrier.