Study of CHR-3996 in combination with tosedostat in subjects with multiple myeloma

Phase 1

Completed

Conditions: Multiple myeloma
Cancer

Registration Number: ISRCTN24989786

Lead Sponsor: niversity of Leeds (UK)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: All

Target Recruitment: 60

Inclusion Criteria

1. Able to give informed consent and willing to follow study protocol
2. Aged 18 years or over
3. Subjects with multiple myeloma diagnosed according to standard criteria, who have been treated with at least one prior therapy, including bone marrow transplantation (if suitable), and currently requiring further treatment due to relapse or non-response
4. ECOG Performance Status less than or equal to 2
5. Required laboratory values within 14 days prior to registration:
5.1. Absolute neutrophil count >1.0 x 109/L, growth factor support is permitted
5.2. Platelet count >25 x 109/L, platelet support is permitted
5.3. Haemoglobin >8.0g/dL, blood support is permitted
5.4. Bilirubin <2 x upper limit of normal (ULN), excluding cases where elevated bilirubin can be attributed to Gilbert?s syndrome
5.5. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <2.5 x ULN; except in subjects with known hepatic involvement, where AST and/or ALT <5.0 x ULN
5.6. Serum creatinine <2.0 x ULN
5.7. Corrected calcium <2.8 mmol/L.
6. Anticipated survival of at least 4 months
7. Evaluable disease per modified International Working Group (IWG) criteria, utilising the following assessments as appropriate:
7.1. Measurement of serum monoclonal protein
7.2. Measurement of serum free light chains
7.3. Measurement of urine M protein (Bence Jones protein) (differential creatinine)
7.4. Detection of plasma cells in bone marrow biopsy or aspirate sample
8. Female subjects of child-bearing potential must have a negative pregnancy test within 24 hours prior to starting therapy and agree to use dual methods of contraception for the duration of the study
9. Male subjects must agree to use a barrier method of contraception for the duration of the study if sexually active with a female of child-bearing potential

Exclusion Criteria

1. Pregnant (positive pregnancy test) or breastfeeding women
2. Patients with high urinary light chain levels (> 1g/24 hours)
3. Previous anti-tumour therapies, including prior experimental agents or approved anti-tumour small molecules and biologics within 28 days before the start of protocol treatment (or a longer period depending on the defined characteristics of the agents)
4. Steroid therapy to stop rapid relapse during this period is permitted, but must be stopped 7 days prior to study drug administration
5. Bisphosphonates for bone disease and radiotherapy for palliative intent are also permitted
6. Concurrent or previous malignancies (<12 months post end of treatment) at other sites with the exception of appropriately treated localised epithelial skin or cervical cancer
7. Patients with histories (=12 months) of other tumours may be entered
8. Poorly controlled or serious medical or psychiatric illness that, in the Investigator?s opinion, is likely to interfere with participation and/or compliance in this clinical study
9. Patients with significant cardiovascular disease (e.g. history of congestive heart failure requiring therapy, presence of severe valvular heart disease, presence of an atrial or ventricular arrhythmia requiring treatment, uncontrolled hypertension, a history of QTc abnormalities or with QTcF intervals >450 msec)
10. Active symptomatic fungal, bacterial, and/or viral infection including active human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis
11. Gastrointestinal disorders that may interfere with absorption of the study drug
12. Abnormal plasma potassium, calcium or magnesium levels (CTCAE v4 Grade 3 or greater) despite therapy

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1. Dose escalation phase:<br>1.1. To determine the maximum tolerated dose (MTD) of CHR-3996 and tosedostat, administered in combination, in subjects with relapsed or refractory multiple myeloma.<br>1.2. We define the MTD to be the dose where at least 2/3 or at least 2/6 patients have a DLT. Therefore the dose taken to the expansion phase will be the MTD-1, or dose level 5 if this highest dose level is reached in the dose escalation phase and no MTD is found. This dose, taken forward to the expansion phase, will be called the recommended dose (RD).<br>2. Dose expansion phase:<br>To estimate the response rate (stable disease or better) after four cycles of CHR-3996 and tosedostat at the RD identified in the dose escalation phase

Secondary Outcome Measures

Name	Time	Method
1. To estimate the safety profile of CHR-3996 and tosedostat administered in combination in subjects with relapsed or refractory multiple myeloma<br>2. To estimate maximum response within six cycles of therapy<br>3. To estimate maximum response to therapy overall<br>4. To estimate time to maximum response from therapy<br>5. To estimate progression-free survival<br>6. To estimate overall survival<br>7. To determine the number of patients with CHR-3996 or tosedostat dose reductions<br>8. To assess compliance to therapy until toxicity, intolerance or progression<br>9. To assess the pharmacokinetic and pharmacodynamic profile of CHR-3996 when administered in combination with tosedostat

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