| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Module 1A: All solid malignancies
Module 1B: Solid malignancies, potentially including TNBC, SCLC, CRPC, ovarian cancer patients, and other appropriate cancer indications.
Module 1B-1 (TNBC): Metastatic or recurrent TNBC
Module 2: Metastatic or locally advanced HR+ and HER2- breast cancer in patients who had previously received an aromatase inhibitor and a CDK4/6 inhibitor
Module 4: All solid malignancies |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Module 1A: To select the CT7001 dose(s) and schedule(s) for further clinical evaluation in patients with advanced solid malignancies.
Module 1B: To assess the biological and anti-tumour activity of CT7001, given as a monotherapy.
Module 1B-1 (TNBC): To further characterize the safety and tolerability of CT7001 and determine the most appropriate dosing regimen for subsequent Phase 2 testing (definitive RP2D).
Module 2A: To determine the recommended Phase 2 dose of CT7001 given in combination with fulvestrant at 500 mg
Module 2B: To compare the efficacy of CT7001 given in combination with fulvestrant versus fulvestrant plus placebo.
Module 2C: To evaluate the efficacy of CT7001 combined with fulvestrant in patients whose disease had progressed on or after fulvestrant plus placebo in Part B of the study.
Module 4: To evaluate the effect of food on the total and peak exposure of CT7001 when dosed as a capsule formulation to patients with advanced solid malignancies. |
|
| E.2.2 | Secondary objectives of the trial |
M1A:
Characterise CT7001 PK after single dose and at steady state after multiple dosing
Assess biological and anti tumour activity of CT7001
M1B and M1B-1 (TNBC):
Eval. the activity of CT7001 as monotherapy.
Further eval. CT7001 plasma concentrations.
Eval. CYP2D6 polymorphisms in this patient population.
M2:
Eval. safety and tolerability
Eval. CT7001 trough concentrations in combination with fulvestrant compared to historical CT7001 data
Eval. correlations between CT7001 exposures and efficacy/safety findings in patient population
Eval. incidence, genotypes and copy number variation of CYP and drug transporter genes that may be involved in CT7001 metabolism
M2B only:
Compare Patient Reported Outcomes between treatment arms
Eval. fulvestrant plasma concentrations in combination with CT7001 or placebo
M4: No additional objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Core Inclusion Criteria:
1. At least 18 years of age
2. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks
3. Estimated life expectancy of greater than 12 weeks
4. Ability to swallow and retain oral medication
5. Women of childbearing potential must be willing to practice effective contraception (per protocol definition) for the duration of the study and for 6 months after the last dose of CT7001
6. Criteria to identify women not of childbearing potential are defined in the protocol
7. Sexually active male subjects must be willing to use contraception per protocol description
8. Provision of signed and dated, written informed consent before any study-specific procedures, sampling, or analyses, including access to archival tumour tissue.
Host Genetics Research Study: Pharmacogenetics Samples (Optional):
1. Provision of signed and dated, written informed consent for the genetic research.
Module 1A Breast Cancer Cohort additional Inclusion Criteria:
1. Histological, radiological or cytological confirmation of breast cancer not considered to be appropriate for further standard treatment.
Module 1A Breast Cancer or Solid Tumour Cohort additional Inclusion Criteria:
1. At least one tumour suitable for repeat biopsy from the same lesion.
Module 1B additional Inclusion Criteria:
1. Histological, radiological or cytological confirmation of metastasis or locally advanced tumour not considered to be appropriate for further standard treatment
2. At least one line of systemic anti-cancer therapy.
3. Disease must be measurable by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1), per protocol description.
Module 1B-1 (TNBC) additional Inclusion Criteria:
1. Histologically confirmed carcinoma of the breast not expressing oestrogen receptor (ER) and progesterone receptor (PgR) and negative for human epidermal growth factor receptor 2 (HER2), per protocol description
2. Metastatic or locally advanced disease not amenable to resection or radiation therapy with curative intent with documented progressive disease on or within 6 months of most recent prior chemotherapy.
3. Disease must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST, version 1. 1), per protocol description
Module 2 will have standalone eligibility criteria with the principal inclusion defined as below:
1. Women 18 years of age or older who are either:
o post-menopausal or pre/peri-menopausal. as defined by one of the following criteria:
OR
o Pre/peri-menopausal, i.e., not meeting the criteria for being postmenopausal, if amenable to treatment with the LHRH agonist goserelin.
5. Histologically confirmed diagnosis of carcinoma of the breast with evidence of metastatic or locally advanced disease, not amenable to resection or radiation therapy with curative intent.
6. Documentation of ER-positive and/or PgR-positive tumour based on most recent tumour biopsy utilizing an assay consistent with local standards.
7. Documentation of HER2 negativity based on local testing on most recent tumour biopsy.
8. Measurable disease as defined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
9. Patients must have documented objective disease progression while on or within 6 months after the end of the most recent therapy.
10. Patients must have received an aromatase inhibitor together with a CDK4/6 inhibitor in the same line of therapy for the treatment of:
o locally advanced or metastatic disease or
o early breast cancer, if the disease-free interval, between initiation of adjuvant therapy and first line treatment of locally advanced or metastatic disease was < 12 months.
13. Ability to swallow and retain oral medication and receive intramuscular injections
Module 2C additional Inclusion Criteria:
Patients must have received fulvestrant plus placebo in Part B of the study and must have objective disease progression while on or within 2 months after the end of study therapy in Part B with fulvestrant and placebo.
Module 4 additional Inclusion Criteria:
1. Subjects must be able to eat a high-fat meal within a 30-minute period, as provided by the study site. |
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| E.4 | Principal exclusion criteria |
Core Exclusion Criteria:
1. Any other malignancy which has been active or treated within the past 3 years, with the exception per protocol description.
2. Any unresolved toxicity (except alopecia) from prior therapy of ≥ Grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE).
3. Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring steroids for at least 4 weeks before the first dose of IP.
4. Refractory nausea and vomiting, chronic GI diseases 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 cytotoxic treatment for the malignancy per protocol description
13. Receipt of noncytotoxic treatment for the malignancy within 5 half-lives of the drug before the first dose of IP
14. Receipt of corticosteroids per protocol description
15. Receipt of any small-molecule investigational medicinal product (IMP) per protocol description
16. Receipt of any biological or non-biological anti-cancer medicine per protocol description
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 activity per protocol description
18. Receipt of a blood transfusion (blood or blood products) per protocol description
19. Known hypersensitivity to CT7001 or any excipient of the product
20. Impaired hepatic or renal function
21. Liver function deteriorating in a manner per protocol description
22. Other evidence of impaired hepatic synthesis function
23. Inadequate bone marrow reserve or organ function
24. Persistent severe pancytopenia due to previous therapy rather than to disease
25. Cardiac dysfunction
26. Mean resting QT interval corrected for heart rate by the Fridericia formula (QTcF) > 470 msec
27. Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG. Controlled atrial fibrillation (AF) is permitted
28. Any factor that increases the risk of QTc prolongation or of arrhythmic events (e.g. per protocol description)
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.
Host Genetics Research Study: Pharmacogenetics Samples (Optional), Exclusion Criteria
1. Allogenic bone marrow transplant.
2. Non-leucocyte-depleted whole blood transfusion within 120 days of the date of the genetic sample collection.
Additional Exclusion Criteria (Module 1 Part A)
International normalised ratio (INR) ≥ 1.5.
Module 1B: No additional exclusion criteria to core.
Module 1B-1 (TNBC) additional Exclusion Criteria:
1. More than three lines of chemotherapy for metastatic and/or locally advanced disease.
2. Advanced, symptomatic, visceral metastases if risk of life-threatening complications in the short term
Module 2
1. Prior therapy with fulvestrant.
2. More than 2 lines of endocrine treatment for locally advanced or metastatic disease.
3. Advanced visceral metastases if risk of life-threatening complications in the short term
4. Known symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease.
5. Known hypersensitivity to CT7001, fulvestrant or any excipient of the investigational products.
6. Diagnosis of any other malignancy within 3 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
7. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Carrick employees directly involved in the conduct of the trial.
Module 4 additional Exclusion Criteria:
1. Subjects who were unable to fast for at least 10 hours. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Module 1A:
• AEs
• Clinical laboratory results (haematology, serum chemistry, coagulation, urinalysis)
• Physical examination findings
• ECOG performance status
• ECG parameters (heart rate, PR interval, QRS complex, QT interval, and QTcF)
• Weight
• Vital signs (supine systolic and diastolic blood pressure and pulse, temperature respiratory rate, oxygen saturation)
Module 1B and 1B-1 (TNBC): Type, incidence, severity (as graded by CTCAE v5.0), seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities.
Module 2A: Dose-limiting toxicities and type, incidence, severity (as graded by CTCAE v5.0), seriousness and relationship to study medications of adverse events (AEs) and any laboratory abnormalities.
Module 2B:
Progression-Free Survival (PFS) as assessed by the investigator. As supportive analysis, PFS will also be assessed by BICR.
Module 2C:
Objective Response (complete or partial response) as assessed by the investigator.
Module 4: AUC0-∞ and Cmax in relation to the effect of food on the total and peak exposure of CT7001. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Modules 1A and 1B: Weekly assessment in first two cycles and every three weeks in subsequent cycles.
Module 2: Assessed every 2 weeks in the first two cycles and every four weeks in subsequent cycles
Module 4: PK assessments recorded over a Feed/Fast crossover, 12-day period. |
|
| E.5.2 | Secondary end point(s) |
Module 1A:
• PK Parameters for CT7001
• Biological Activity Parameters (Biomarkers)
• Anti-tumour Activity
Module 1B and 1B-1 (TNBC):
• Objective response rate (ORR)
• Duration of response (DOR)
• Disease control (DC: CR or PR or SD ≥24 weeks)
• Best percent tumour size change
• Progression-free survival (PFS)
• Trough plasma concentrations of CT7001
Module 4: No additional secondary endpoints to core protocol.
Module 2 all study parts:
• Duration of response (DOR)
• Clinical Benefit Response (CBR) (complete or partial response, or stable disease ≥24 weeks
• Trough plasma concentrations of CT7001
• Incidence and type of genotypes and copy number variation of CYP2D6, other CYP genes and drug transporter genes that may be involved in the metabolism of CT7001
Module 2A and 2B only:
• Objective response rate (ORR)
• Trough plasma concentrations of fulvestrant
Module 2A and 2C only:
• Best percent change in tumour size
Module 2B only:
• Patient Reported Outcome endpoints such as health related quality of life scores:
o EuroQol (EQ-5D) Score; European Organisation for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30); European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23]). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Module 1A
Efficacy (anti-tumour activity): Every 6 weeks on therapy, every 3 months during follow up.
Biomarkers assessed at screening, cycle 0, cycle 1, and Day 1 of each subsequent cycle, and at End of Treatment.
PK assessed at cycle 0, 1, 2, 3 and every other cycle onwards, and at End of Treatment.
Module 1B 1B-1
Efficacy (ORR, DOR, DC, best % tumour size change, PFS): Every 8 weeks on therapy, every 3 months during follow up.
PK assessed at all cycles, and at End of Treatment.
Module 2
Efficacy (ORR, DOR, CBR, best percent tumour size change): every 8 weeks on therapy, every 12 weeks during follow up.
PK assessed at all cycles, and at End of Treatment.
Incidence/type of genotypes/ copy number variation of CYP and drug transporter genes assessed at pre-dose cycle 1 only. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Trial with multiple modules |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Multiple modules and one double-blind placebo controlled module (2B) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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