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Modular Study to Evaluate CT7001 Alone in Cancer Patients With Advanced Malignancies

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ClinicalTrials.gov Identifier: NCT03363893
Recruitment Status : Recruiting
First Posted : December 6, 2017
Last Update Posted : June 10, 2019
Sponsor:
Information provided by (Responsible Party):
Carrick Therapeutics Limited

Brief Summary:
This is a modular, Phase I/II, multicentre study to investigate the optimal monotherapy dose of CT7001 in advanced solid malignancies (Module 1A) and to further investigate the monotherapy dose of CT7001 in specific participant groups (Module 1B). Further modules will be added as substantial protocol amendments. A food-effect study of CT7001 monotherapy in advanced solid malignancies (Module 4) is ongoing. A study of combination doses of CT7001 with fulvestrant in hormone receptor-positive (HR+ve) / human epidermal growth factor-2 negative (HER2-ve) breast cancer (Module 2) is planned to start in 2019.

Condition or disease Intervention/treatment Phase
Advanced Solid Malignancies Drug: CT7001 Drug: CT7001 in combination with fulvestrant Phase 1 Phase 2

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. Part A has now completed recruitment (39 participants dosed) and has identified the MBAD as 120mg once daily and the MTD as 360mg once daily. The recommended dose to take forward to Phase II is 360mg.
  • Part B: To refine the safety, tolerability, and PK and PD profiles of CT7001 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) will recruit up to 50 participants treated with a 360mg daily dose of CT7001 as monotherapy. Recruitment is currently open.
    • Part B, Cohort 2, Prostate Cancer (M1B-2 CRPC) will recruit up to 25 participants treated with a 360mg daily dose of CT7001 as monotherapy. Recruitment is not yet open.
    • Additional Module 1B Cohorts of up to 25 participants each may be added in the future.

Module 4 is a study investigating the effect of food on the PK of CT7001 monotherapy in participants with advanced solid malignancies. Up to 24 participants will be recruited. Recruitment is currently open.

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 will recruit up to 75 participants and will dose CT7001 in combination with fulvestrant. Part B will be single-blind, randomized and placebo-controlled.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Modular design
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Modular, Multipart, Multiarm, Open-label, Phase I/II Study to Evaluate the Safety and Tolerability of CT7001 Alone and in Combination With Anti-cancer Treatments in Patients With Advanced Malignancies
Actual Study Start Date : November 14, 2017
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Fulvestrant

Arm Intervention/treatment
Experimental: Module 1 Part A
Participants with advanced solid tumours receive CT7001 as oral monotherapy, in ascending dose cohorts, to identify the maximum tolerated dose (MTD), minimally biologically active dose (MBAD) and recommended dose for Phase II testing (RP2D).
Drug: CT7001
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression

Experimental: Module 1 Part B
Participants with advanced solid tumours that may include, but is not limited to, castrate-resistant prostate cancer (CRPC), small cell lung cancer (SCLC) or ovarian cancer, will receive CT7001 as oral monotherapy at the dose, frequency and schedule recommended from Module 1 Part A.
Drug: CT7001
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression

Experimental: Module 1 Part B-1 TNBC Expansion
Participants with locally advanced or metastatic triple-negative breast cancer (TNBC) will receive CT7001 as oral monotherapy at the dose, frequency and schedule recommended from Module 1 Part A.
Drug: CT7001
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression

Experimental: Module 2 Part A
Participants with locally advanced or metastatic HR+ve and HER2-ve breast cancer will receive CT7001 oral monotherapy at either 240mg (Cohort 1) or 360mg (Cohort 2) in combination with fulvestrant.
Drug: CT7001 in combination with fulvestrant
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression in combination with fulvestrant given as 2 x 250mg intramuscular (IM) gluteal injections on Day 1, Day 15, Day 28 and every 28 days thereafter

Experimental: Module 2 Part B
Participants with locally advanced or metastatic HR+ve and HER2-ve breast cancer will be randomized to receive CT7001 or matching placebo as oral monotherapy at the dose determined in Module 2 Part A, in combination with fulvestrant.
Drug: CT7001 in combination with fulvestrant
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression in combination with fulvestrant given as 2 x 250mg intramuscular (IM) gluteal injections on Day 1, Day 15, Day 28 and every 28 days thereafter

Experimental: Module 2 Part C
Participants with locally advanced or metastatic HR+ve and HER2-ve breast cancer who were enrolled to the placebo arm in Module 2 Part B will, on progression of disease, receive CT7001 oral monotherapy in combination with fulvestrant.
Drug: CT7001 in combination with fulvestrant
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression in combination with fulvestrant given as 2 x 250mg intramuscular (IM) gluteal injections on Day 1, Day 15, Day 28 and every 28 days thereafter

Experimental: Module 4
Participants with advanced solid tumours will receive CT7001 oral monotherapy in a randomized, balanced, single-dose, two-treatment (fed v fasting), two-period, two-sequence crossover study followed by once daily continuous dosing.
Drug: CT7001
Cyclin-dependent kinase 7 (CDK7) inhibitor given orally once daily until disease progression




Primary Outcome Measures :
  1. Treatment-Emergent Adverse Events and Laboratory Abnormalities (Safety and Tolerability) [ Time Frame: Screening to end of study ]
    Type, incidence and severity


Secondary Outcome Measures :
  1. Maximum Plasma Concentration of CT7001 (and Fulvestrant, where applicable) (Cmax) [ Time Frame: After the first dose and during the dosing period ]
  2. Area Under the Curve (AUC) [ Time Frame: After the first dose and during the dosing period ]
  3. Biological Activity Parameters (Biomarkers) in Peripheral Blood [ Time Frame: Screening to end of treatment ]
  4. Anti-tumour Activity according to RECIST v1.1 [ Time Frame: Baseline until disease progression or withdrawal from the study ]
  5. Objective Response Rate (ORR) [ Time Frame: Baseline until disease progression or withdrawal from the study ]
  6. Progression-Free Survival (PFS) [ Time Frame: Baseline until disease progression or withdrawal from the study ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 12 months (Module 2) after the last dose of CT7001
  5. Men, if sexually active, must be willing to use condoms 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 cytotoxic treatment for the malignancy within 28 days 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 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
    6. International normalised ratio (INR) ≥ 1.5
  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 biopsy

Additional Module 1B Inclusion Criteria

  1. Histological or cytological confirmation of metastasis or locally advanced tumour
  2. At least one line of systemic anti-cancer therapy
  3. Disease measurable by RECIST v1.1

Additional Module 1B-1 (TNBC Expansion) Inclusion Criteria:

  1. Histologically-confirmed carcinoma of breast not expressing oestrogen receptor (ER) or progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2)
  2. Documented disease progression on or within 6 months of most recent cytotoxic chemotherapy
  3. Disease measurable by RECIST v1.1
  4. Must have received prior cytotoxic chemotherapy with a taxane and an anthracycline
  5. Must have received at least one cytotoxic chemotherapy for metastatic/locally advanced disease

Additional Module 1B-1 (TNBC Expansion) Exclusion Criteria:

  1. No more than three lines of cytotoxic chemotherapy for metastatic/locally advanced disease
  2. No advanced, symptomatic visceral metastases
  3. No known symptomatic central nervous system (CNS) metastases, carcinomatous meningitis
  4. Prior exposure to CT7001
  5. 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

Additional Module 2 Inclusion Criteria:

  1. Women only
  2. Pre- or peri-menopausal women must have initiated goserelin at least 28 days prior to first dose of CT7001/placebo
  3. Histologically-confirmed, metastatic or locally advanced, ER+ve and/or PG+ve and HER2-ve breast cancer
  4. Disease measurable by RECIST v1.1
  5. Documented objective disease progression while on, or within 6 months after the end of, the most recent therapy
  6. Must have received an aromatase inhibitor for locally advanced or metastatic disease or for treatment of early breast cancer if the disease-free interval was <12 months
  7. Must have received a CDK4/6 inhibitor for locally advanced or metastatic breast cancer

Additional Module 2 Exclusion Criteria:

  1. Prior therapy with fulvestrant
  2. More than 2 lines of endocrine treatment for locally advanced or metastatic disease
  3. Known hypersensitivity to CT7001, fulvestrant or any excipient of the investigational products
  4. 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

Additional Module 4 Inclusion Criteria:

  1. Patients must be able to eat a high-fat meal, as provided by the study site, within a 30-minute period
  2. Histological, radiological or cytological confirmation of an advanced non-haematological malignancy not considered to be appropriate for further standard treatment

Additional Module 4 Exclusion Criteria:

1. Patients who were unable to fast for at least 10 hours


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03363893


Contacts
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Contact: Glen Clack, MD +447765898619 glen.clack@carricktherapeutics.com
Contact: Manfred Lehnert, MD +353(86)7036789 manfred.lehnert@carricktherapeutics.com

Locations
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United States, New York
Research Site Not yet recruiting
New York, New York, United States, 10065
United Kingdom
Research Site Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Research Site Recruiting
Glasgow, United Kingdom, G12 0YN
Research Site Recruiting
London, United Kingdom, W2 1NY
Research Site Recruiting
Manchester, United Kingdom, M20 4BX
Research Site Recruiting
Oxford, United Kingdom, OX3 7LE
Research Site Not yet recruiting
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
Carrick Therapeutics Limited
Investigators
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Principal Investigator: Matthew Krebs, MBChB PhD The Christie Hospital, Manchester, UK

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Responsible Party: Carrick Therapeutics Limited
ClinicalTrials.gov Identifier: NCT03363893     History of Changes
Other Study ID Numbers: CT7001_001
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: June 10, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Carrick Therapeutics Limited:
Neoplasms
Additional relevant MeSH terms:
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Neoplasms
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs