Clinical Trials /

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

NCT02437227

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

A Phase I, First in Man Study to Evaluate the Safety and Tolerability of a panRAF Inhibitor (<span class="go-doc-concept go-doc-intervention">CCT3833</span>/BAL3833)in Patients With Solid Tumours

Title

  • Brief Title: A Phase I, First in Man Study to Evaluate the Safety and Tolerability of a panRAF Inhibitor (CCT3833/BAL3833)in Patients With Solid Tumours
  • Official Title: A Phase 1, First in Man, Dual Centre, Open-label Dose Escalation Study With Expansion to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of CCT3833 (BAL3833), a panRAF Inhibitor, Given Orally in Patients With Advanced Solid Tumours, Including Metastatic Melanoma
  • Clinical Trial IDs

    NCT ID: NCT02437227

    ORG ID: 4232

    Trial Conditions

    Melanoma

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    CCT3833 Experimental: CCT3833

    Trial Purpose

    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.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Experimental: CCT3833 Experimental The starting dose of CCT3833 is 20 mg, taken as two 10 mg capsules. The starting schedule is a once daily continuous dosing schedule, but other dosing regimens may be considered depending on tolerability and exposures.The first dose of continuous dosing defines Cycle 1 Day 1. All treatment cycles have a duration of 28 days. CCT3833

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Establishing the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of CCT3833.

    Assessing the safety and tolerability profile of CCT3833. (adverse event)

    Secondary Outcome Measures

    To determine the pharmacokinetic profile of CCT3833 in humans. (plasma levels of CCT3833)

    To explore possible anti-tumour activity of CCT3833 in patients with advanced solid tumours.(measurable response (clinical or radiological) in any of the patients, as determined by the RECIST criteria v1.1)

    Determining the correlation between PK exposures and tolerability and/or efficacy (i.e. defining the safe therapeutic range).

    Trial Keywords