Advanced Solid Malignancies
Conditions
Keywords
Neoplasms
Brief summary
This is a modular, Phase I/II, multicentre study to investigate CT7001 monotherapy in advanced solid malignancies and to further investigate CT7001 as monotherapy or in combination with standard therapy in specific participant groups with Triple Negative Breast Cancer (TNBC), Castrate Resistant Prostate Cancer (CRPC) and in combination with fulvestrant for patients with hormone receptor-positive (HR+ve) / human epidermal growth factor-2 negative (HER2-ve) breast cancer.
Detailed description
Module 1 comprises two sequential parts: * Part A: First-in-human (FiH) dose escalation investigating the safety and tolerability of CT7001 to identify the minimum biologically active dose (MBAD) and maximum tolerated dose (MTD). Part A also includes a cohort expansion for breast cancer participants only: this includes sequential tumour biopsies for evaluation of pharmacokinetic (PK), pharmacodynamic (PD) and tumour responses. The module is completed. * Part B: To refine the safety, tolerability, and PK and PD profiles of CT7001 monotherapy in participants with advanced solid malignancies from up to four tumour- specific cohorts, which may include, but is not limited to, triple-negative breast cancer, ovarian cancer, small-cell lung cancer and prostate cancer. * Part B, Cohort 1, Triple-Negative Breast Cancer (M1B-1 TNBC) treated with CT7001 as monotherapy. The module is completed. * Part B, Cohort 2, Prostate Cancer (M1B-2 CRPC) treated with CT7001 as monotherapy. The module is completed. * Module 2 is a Phase Ib/II, 3-part safety and efficacy study in participants with hormone- receptor positive (HR+ve) and human epidermal growth factor-2 negative (HER2-ve) breast cancer. This module includes dosing CT7001 in combination with fulvestrant. Module 2 was planned to comprise of 3 parts; Part A (open-label, single-arm, ascending dose study), Part B (double blinded, randomised, placebo-controlled study) and Part C (crossover from Part B). However, only Module 2 Part A was initiated and completed. Therefore, further sections of this record only reflect Module 2 Part A information. * Module 4 is a study investigating the effect of food on the PK of CT7001 monotherapy in participants with advanced solid malignancies. The module is completed. * Module 6 was planned as a Phase 1 study to explore the tolerability of, and the total and peak exposure of, an enteric capsule formulation of CT7001 \[CT7001(EC)\], when given as monotherapy to patients with advanced solid malignancies. Module 6 was not initiated.
Interventions
DRUGCT7001
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression
DRUGFulvestrant
Administered as 2 x 250mg intramuscular (IM) gluteal injections on Day 1, Day 15, Day 28 and every 28 days thereafter.
Sponsors
Carrick Therapeutics Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Modular design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Core Inclusion Criteria: 1. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks 2. Estimated life expectancy of greater than 12 weeks 3. Ability to swallow and retain oral medication 4. Women either of non-childbearing potential or of childbearing potential willing to practice effective contraception for the duration of the study and for 6 months (Module 1, Module 4) and 24 months (Module 2) after the last dose of CT7001 5. Sexually active male patients must be willing to use condoms with all sexual partners for the duration of the study and for 3 months after the last dose of CT7001. 6. Provision of signed and dated, written informed consent Core
Exclusion criteria
1. Any other malignancy that has been active or treated within the past 3 years, with the exception of cervical intraepithelial neoplasia and non-melanoma skin cancer 2. Any unresolved toxicity (except alopecia) from prior therapy of ≥ CTCAE Grade 2 3. Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the first dose of investigational product (IP) 4. Refractory nausea and vomiting, chronic gastrointestinal (GI) disease or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of CT7001 5. Uncontrolled seizures 6. Active infection requiring systemic antibiotic, antifungal, or antiviral medication 7. Severe or uncontrolled medical condition or psychiatric condition 8. Active bleeding diatheses 9. Renal transplant 10. Known hepatitis B, hepatitis C, or human immunodeficiency virus infection 11. Breastfeeding or pregnancy 12. Receipt of systemic cytotoxic treatment for the malignancy within 28 days or ≤ 5 half-lives, whichever is shorter before the first dose of IP 13. Receipt of non-cytotoxic treatment for the malignancy within 5 half-lives of the drug before the first dose of IP 14. Receipt of corticosteroids (at a dose \> 10 mg prednisone/day or equivalent) within 14 days before the first dose of IP 15. Receipt of any small-molecule investigational medicinal product (IMP) within 28 days or ≤ 5 half-lives, whichever is shorter before the first dose of IP 16. Receipt of any biological IMP (e.g., immune checkpoint blockers, antibodies, nanoparticles) within 42 days before the first dose of IP 17. Receipt of St John's Wort within 21 days before the first dose of IP or of another concomitant medication, herbal supplement, or food that is a strong inhibitor or inducer of CYP3A4, CYP2C19, CYP2D6, or P-glycoprotein (PGP) activity within 14 days before the first dose of CT7001 18. Receipt of a blood transfusion (blood or blood products) within 14 days before the first dose of IP 19. Known hypersensitivity to CT7001 or any excipient of the product 20. Impaired hepatic or renal function as demonstrated by any of the following laboratory values: 1. Albumin \< 30 g/L 2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × the upper limit of normal (ULN) 3. \> 5.0 × ULN for patients with liver metastases 4. Total bilirubin \> 1.5 × ULN 5. Serum creatinine \> 1.5 × ULN 21. Liver function deteriorating in a manner that would likely make the participant meet the AST, ALT, or bilirubin levels specified above at the time of the first dose of IP 22. Other evidence of impaired hepatic synthesis function 23. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: 1. Absolute neutrophil count (ANC) \< 1.5 × 10\^9/L 2. Platelet count \< 100 × 10\^9/L 3. Haemoglobin \< 90 g/L 24. Persistent (\> 4 weeks) severe pancytopenia due to previous therapy rather than to disease (ANC \< 0.5 × 10\^9/L or platelets \< 50 x 10\^9/L) 25. Cardiac dysfunction (defined as myocardial infarction within 6 months of study entry, New York Heart Association Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias, or left ventricular ejection fraction \< 55 percent) 26. Mean resting QT interval corrected for heart rate by the Fridericia formula (QTcF) \> 470 msec obtained from 3 electrocardiograms (ECGs) obtained within 5 minutes of each other prior to the first dose 27. Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (e.g., complete left bundle branch block, third degree heart block). Controlled atrial fibrillation (AF) is permitted 28. Any factor that increases the risk of QTc prolongation or of arrhythmic events (e.g., heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age) 29. In the opinion of the Investigator, unlikely to comply with study procedures, restrictions, or requirements 30. A history of haemolytic anaemia or marrow aplasia 31. Has received a live-virus vaccination within 28 days or less of planned treatment start Additional Module 1A Inclusion Criteria: 1. Histological, radiological or cytological confirmation of an advanced non-haematological malignancy not considered to be appropriate for further standard treatment 2. Module 1A biopsy cohort only : at least one tumour suitable for repeat biopsy Additional Module 1A
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-Emergent Adverse Events and Laboratory Abnormalities (Safety and Tolerability) | Screening to end of study (28-35 calendar days after end of treatment). End of treatment at disease progression, unacceptable toxicity or withdrawal of consent. Average time on study 142.6 days (range 9 - 1135 days) | Treatment-emergent adverse events (TEAEs) are defined as those AEs which occur from Cycle 0 Day 1/Cycle 1 Day 1 of the study module to 28 days after the last dose of CT7001 in a module. Results reported below for Participants with one or more related TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration of CT7001 (Cmax) | After the first dose and during the dosing period (from the time of dose administration to 24 hours) for Module 1A cohorts. Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24, 48, 72, 120 and 168 hours post dose for Module 4 Cohorts. | Cmax is the maximum observed plasma concentration of CT7001 following oral dosing. |
| Area Under the Curve (AUC) | After the first dose and during the dosing period (from the time of dose administration to 24 hours) for Module 1A. Pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24, 48, 72, 120 and 168 hours post dose for Module 4 Cohorts. | Area under the plasma concentration-time curve representing the total drug exposure over time. |
| Mean Trough Plasma Pharmacokinetic Concentrations for CT7001 | From enrolment (Day 1) through to disease progression, unacceptable toxicity or withdrawal of consent, whichever came first (EOT). Assessed up to 1135 days. On study pre-dose sampling for all modules (see outcome measure description). | Mean Trough Plasma Pharmacokinetic Concentrations is the lowest concentration of a drug in the bloodstream during a dosing interval. Timeframe: On study sampling: M1A - Day 1, 8, 15, 22, 29, 43, 50, every 21 days thereafter and EOT. M1B-1 and M1B-2: Day1, 8, 22, every 21 days thereafter and EOT. M2A: Day1, 15, 29, 57, every 56 days thereafter and EOT. M4: Day 1, 8, 15, 22, 29, 36, every 21 days thereafter and EOT. |
| Mean Trough Plasma Pharmacokinetic Concentrations for Fulvestrant (Module 2A) | From enrolment through to disease progression, unacceptable toxicity or withdrawal of consent, whichever came first (EOT). Pre-dose sampling at Day 1, 15, 29, 57 and every 56 days thereafter and EOT. Assessed up to 848 days. | Mean trough plasma PK concentrations refer to the lowest concentration of a drug in the bloodstream during a dosing interval. |
| Anti-tumour Activity According to RECIST v1.1-Best Objective Response | From enrolment (Day 1) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1135 days (162 weeks). Frequency in outcome measure description. | Antitumour activity endpoints were analysed using the evaluable for Response population (any patient with at least one post baseline RECIST assessment). Best objective response is defined as the best response recorded from the start of study treatment to the end of treatment, including any assessments for confirmation after the end of treatment. Percentage of participants with each response calculated was based on the total number of participants with a baseline RECIST assessment. Timeframe: Scan frequency - Modules 1A and 4 (every 6 weeks); Modules 1B-1 and 2A (every 8 weeks first year, every 12 weeks thereafter); Module 1B-2 (every 8 weeks for the 6 months, every 12 weeks thereafter). |
| Anti-tumour Activity According to RECIST v1.1-Progression Free Survival | From enrolment (Day 1) until the date of first documented progression or date of death from any cause, whichever came first. Modules 1B-1 and 2A: every 8 weeks first year, every 12 weeks thereafter) assessed up to 848 days (121 weeks). | Antitumour activity endpoints were analysed using the evaluable for Response population based on RECIST assessment. Progression free survival is defined as the time from start of treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant had withdrawn from therapy or had received another anti-cancer therapy prior to progression. Participants who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. |
| Anti-tumour Activity According to RECIST v1.1-Clinical Benefit Rate (CBR) | From enrolment (Day 1) until the date of first documented progression or date of death from any cause, whichever came first. Module 2A: every 8 weeks first year, every 12 weeks thereafter) assessed up to 848 days (121 weeks). | Antitumour activity endpoints were analysed using the evaluable for Response population based on RECIST assessment. Clinical Benefit Rate (CBR) is defined as the percentage of subjects with a confirmed objective response of complete response or partial response, or stabilisation of disease for at least 24 weeks. |
Countries
United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORMatthew Krebs, MBChB PhD
The Christie Hospital, Manchester, UK
Participant flow
Recruitment details
This study recruited participants at least 18 years of age with histological or cytological confirmation of an advanced malignancy, with an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and an estimated life expectancy greater than 12 weeks.
Pre-assignment details
A total of 174 participants were recruited, of which 124 participants were enrolled and went on to receive study treatment with CT7001. Of the 174 participants screened, 50 participants did not receive study treatment, of which 46 participants did not meet the study enrolment criteria and 4 participants withdrew from the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 45 Participants |
| Age, Categorical Between 18 and 65 years | 79 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 107 Participants |
| Region of Enrollment United Kingdom | 6 participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 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 | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 1 / 12 | 0 / 6 | 0 / 12 | 0 / 8 | 2 / 23 | 0 / 11 | 0 / 6 | 1 / 25 | 0 / 6 | 0 / 8 | 0 / 7 | 0 / 7 | 0 / 8 | 1 / 7 |
| other Total, other adverse events | 6 / 6 | 12 / 12 | 6 / 6 | 12 / 12 | 8 / 8 | 23 / 23 | 11 / 11 | 6 / 6 | 25 / 25 | 2 / 6 | 7 / 8 | 5 / 7 | 5 / 7 | 8 / 8 | 7 / 7 |
| serious Total, serious adverse events | 1 / 6 | 4 / 12 | 1 / 6 | 3 / 12 | 3 / 8 | 9 / 23 | 2 / 11 | 2 / 6 | 8 / 25 | 0 / 6 | 0 / 8 | 0 / 7 | 0 / 7 | 0 / 8 | 4 / 7 |
Outcome results
None listed