A Phase I, First in Man Study to Evaluate the Safety and Tolerability of a panRAF Inhibitor (CCT3833/BAL3833)in Patients With Solid Tumours

The study is a first in man, dose escalation study to evaluate the safety, tolerability and how the drug works in the body in patients with all solid tumours. The aim of this study is to determine the most effective dose of the study drug that can then be further investigated in patients with advanced melanoma.

Metastatic malignant melanoma is the 5th most common cancer in the UK, with a notable proportion of young patients. The development of immunotherapies (such as Ipilimumab), and targeted therapies (such as Vemurafenib, a BRAF inhibitor) have resulted in improved survival outcomes for patients but is still only measured in months and not years. These targeted therapies are also only useful for patients with the relevant genetic mutation, leaving a significant proportion of patients without targeted therapy options. The need for more effective (and ideally curative) melanoma treatments remains. The Institute of Cancer Research, with funding from the Wellcome Trust, have created and developed a new panel of inhibitors that aim to more effectively terminate the growth, spread and survival signals that sustain the cancer. The broader targets allow patients possessing a range of genetic mutations to potentially benefit from this targeted therapy. It is hoped that these drugs could be used as both primary therapy for treatmentnaive patients as well as rescue therapy for those who have progressed on other targeted therapies.

This is a phase 1 study to evaluate the safety and effectiveness of one of these new compounds, CCT 3833, and to define the maximum tolerated dose in patients with advanced melanoma. The study also aims to examine the way that CCT3833 works within the body. Once the maximum tolerated dose has been established a small number of melanoma patients, with specific mutations and at different treatment option stages, will be treated to gain additional safety information and an initial indication of the possible efficacy of CCT3833 on melanoma tumours.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years or over.
2. Written (signed and dated) informed consent and willing and capable of co-operating with study procedures, treatment and follow-up.
3. Histologically proven advanced or metastatic solid tumours.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Life expectancy of at least 12 weeks.
6. Haematological and biochemical indices (within 7 days before the first dose of CCT3833) within the ranges shown below:

   1. Haemoglobin (Hb) ≥ 9.0 g/dL.
   2. Absolute neutrophil count ≥ 1.5 x 109/L.
   3. Platelet count ≥ 100 x 109/L.
   4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), and Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x (ULN) (or ≤ 5 x ULN if elevated due to tumour).
   5. Calculated creatinine clearance \> 50 mL/min (based on Cockcroft-Gault calculation).
7. Negative pregnancy test for females of child-bearing age.

Inclusion criteria: dose expansion cohort

Patients must meet ALL of the above criteria and additionally meet the following criteria:

1. Histologically proven locally advanced (unresectable) or metastatic melanoma.
2. Documented presence of either BRAF or RAS mutations, as established by validated mutation testing from tumour biopsy.
3. Evidence of measurable disease (according to RECIST v1.1)

Exclusion Criteria:

Patients who meet ANY of the following criteria will not be eligible to participate.

Patients who have had any of the following within the last 4 weeks:

1. Radiotherapy (except for palliative reasons), endocrine therapy (except luteinizing hormone releasing hormone (LHRH) agonists for prostate cancer), immunotherapy or chemotherapy (6 weeks for nitrosoureas, Mitomycin-C and 4 weeks for other investigational medicinal products (IMP)) before treatment. (For patients recruited to Part B (dose expansion) from Part A (dose escalation), prior treatment with CCT3833 during Part A (dose escalation) is permissible.)
2. Major surgery within the last four weeks.
3. Has been a participant in another interventional research study (involving an IMP) within the last 4 weeks, or plans to participate in one whilst taking part in this study. Participation in an observational study would be acceptable.

   Patients who have any of the following:
4. High medical risk because of non-malignant systemic disease including active, uncontrolled infection.
5. Known allergy to any pharmaceutical excipients.
6. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV). Testing for these viruses is not mandatory.
7. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

   1. History or presence of ventricular tachyarrhythmia.
   2. Presence of unstable atrial fibrillation (ventricular response \> 100 bpm); patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria.
   3. Repeated presence of a prolonged QTc interval \> 450 ms at baseline (as calculated by Fridericia method).
   4. Unstable angina pectoris or acute myocardial infarction in the last 12 months prior to starting study drug.
   5. Other clinically significant heart disease (e.g., symptomatic congestive heart failure (LVEF \< 50%); uncontrolled arrhythmia; history of labile hypertension or poor compliance with an antihypertensive regimen).
8. Uncontrolled hypertension that remains uncontrolled on \> 1 antihypertensive agent.
9. Symptomatic brain metastases (if present they must have been stable for \> 3 months). Such patients must not be requiring systemic corticosteroid or enzyme-inducing anticonvulsant therapy.
10. Inability to take oral medication; impairment of GI function or GI disease that could interfere with drug absorption.
11. Have taken potent inducers/inhibitors of CYP3A4 and CYP2C8 liver enzymes within 2 weeks of the first administration of study drug, or have conditions that require the concomitant usage of such drugs during the course of the study.
12. Are taking warfarin as an oral anticoagulant; patients anticoagulated with low molecular weight heparin are not excluded from the trial.
13. Female patients who are pregnant or lactating, or have the ability to become pregnant. However, those female patients who have a negative serum or urine pregnancy test before enrolment and are using highly-effective contraception during the study and for 6 months afterwards, are considered eligible. Highly-effective contraception methods include:

    1. Total abstinence.
    2. Male or female sterilization.
    3. A combination of any two of the following:

    i. Oral, injected or implanted hormonal contraception. ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS). iii. Barrier methods of contraception: condom or diaphragm with spermicidal foam/gel/film/cream/vaginal suppository.
14. Male patients with partners of child-bearing potential, unless they agree to take measures not to father children by using one form of highly effective contraception as defined above, during the study and for 6 months afterwards. Men with pregnant or lactating partners should be advised to use barrier method contraception to prevent exposure to the foetus or neonate.
15. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical study.