Cancer, Melanoma
Conditions
Brief summary
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.
Interventions
DRUGCCT3833
CCT3833 is a poorly soluble crystalline compound. It is multi-polymorphic and one form, designated Form D, has been purified and typically has a particle size of about 15-20 μm. Form D readily absorbs and desorbs water, but is not a hydrate and has been selected as the form to take forward into clinical development.
Sponsors
Royal Marsden NHS Foundation Trust
Institute of Cancer Research, United Kingdom
Wellcome Trust
Biomedical Research Centre for Cancer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation study with expansion. Each dose level constitutes a group/arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Patients With Dose Limiting Toxicities (DLT). | Patients were assessed for DLTs from trial treatment start (cycle 1 day 1) through each of the treatment (28 days) cycles until the patients' final safety follow up at 30 days after last dose for up to 18 months. | Number of patients with DLT in each cohort/dose level. The maximum tolerated dose is the dose at which no more than one patient out of up to six patients at the same dose level experience a highly probably or probably drug-related DLT as defined in the protocol. |
| Assessing the Safety and Tolerability Profile of CCT3833. (Adverse Event) | AEs were graded and recorded from the trial entry confirmation, at the treatment start cycle 1 day 1, at day 1 of each CCT3833 (28 days) cycles, until the patients' final safety follow up at 30 days after last dose for up to 18 months. | Determining causality of each adverse event (AE) to CCT3833 and grade according to National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORJames Larkin, Dr
Royla Marsden NHS Foundation Trust
Participant flow
Recruitment details
Study opened on 15/04/2015 to recruit 31 patients at two sites (Royal Marsden and Christie).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 54.93 years STANDARD_DEVIATION 11.72 |
| Race/Ethnicity, Customized Ethnicity African/Caribbean | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Caucasian | 3 Participants |
| Region of Enrollment United Kingdom | 31 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 4 / 4 | 5 / 6 | 3 / 4 | 4 / 5 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 6 / 6 | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 2 / 3 | 3 / 3 | 1 / 3 | 0 / 3 | 0 / 4 | 2 / 6 | 2 / 4 | 3 / 5 |
Outcome results
None listed