A Trial of CXD101 in Combination With Nivolumab in Patients With Metastatic Microsatellite-Stable Colorectal Cancer (CAROSELL)

A Phase Ib/ II Trial to Assess the Safety and Efficacy of CXD101 in Combination With the PD-1 Inhibitor Nivolumab in Patients With Metastatic, Previously-Treated, Microsatellite-Stable Colorectal Carcinoma

This is a study to assess the safety and efficacy of CXD101 in combination with the PD-1 Inhibitor Nivolumab in patients with metastatic, previously-treated, Microsatellite-Stable (MSS) Colorectal Carcinoma (CRC). The primary hypothesis of this study is that CXD101 and anti-PD1 monoclonal antibody synergise the anti-tumour activity in MSS colorectal cancer patients (~95% of CRC) who do not seem to respond to anti-PD1 or -PD-L1 immunotherapy alone.

Study Overview

• Status: Unknown
• Conditions: Colorectal Neoplasms Malignant
• Intervention / Treatment: Drug: CXD101 in Combination With Nivolumab

Detailed Description

Phase Ib trial: This single-arm dose escalation trial will determine the safety, tolerability and dose limiting toxicities (DLT) and therefore the maximum tolerated dose (MTD) of repeat doses of nivolumab combined with CXD101. The incidence and severity of adverse events (evaluated according to CTCAE version 4.03), vital signs, ECG parameters, biochemistry, haematology and urinalysis will be recorded to determine tolerability.

Dose escalation will proceed as follows:

Dose Level 1 Nivolumab 240 mg iv q 2 weekly; with CXD101 30 mg (20mg mane, 10mg nocte) po for 5 days q 3 weekly (n=3-6) with both drugs commencing on the same day in cycle 1.

Dose Level 2 Nivolumab 240 mg iv q 2 weekly; with CXD101 40mg (20 mg bid) po for 5 days q 3 weekly (n=6) with both drugs commencing on the same day in cycle 1.

A maximum of 15 subjects will be required.

Phase II trial: Following completion of the Phase Ib study, a Phase II CXD101/ nivolumab combination dose will be selected by the Data and Safety Monitoring Committee. Up to a further 40 subjects will then be treated at the selected Phase II CXD101/ nivolumab combination dose. Subjects may continue to receive CXD101/ nivolumab until complete response, disease progression, unacceptable toxicity, withdrawal of consent, or other medical problems supervene.

Efficacy will be measured using Immune Response Evaluation Criteria in Solid Tumours (iRECIST) Imaging studies, typically CT scan of chest, abdomen & pelvis, supplemented by MRI of liver when required, will be performed at Baseline and after every 6 weeks, with objective confirmation of response 6 weeks (+/- 1 week) after observation. Safety parameters will be assessed as in the Phase I study. In addition there will be a series of translational analyses including correlation of tumour biomarker expression with response.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX4 4GA
      • Celleron Therapeutics Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent
• Biopsy-confirmed MSS, MMR-P CRC. It is acceptable for this test to be performed on the archived primary colorectal cancer tissue and repeat biopsy for MSS testing is not required unless assay not yet performed and insufficient material available
• Previous first and second line treatment (unless contra-indicated) including use of oxaliplatin and irinotecan unless documented intolerance of these
• Measurable disease: longest diameter≥10mm (short axis ≥15mm for nodal lesions)
• Age > 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Predicted life expectancy > 3 months
• Adequate organ and bone marrow function: Hb> 10.0g/dL (may be transfused to this level), neutrophils> 1.5x10^9/L and platelets> 100x10^9/L
• Female patients with reproductive potential must have a negative urine and serum pregnancy test prior to starting treatment. Both women of reproductive potential and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 5 months after discontinuation of treatment (i.e., combined oestrogen and progestogen ovulation inhibition; progestogen-only ovulation inhibition; intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; or vasectomised partner). Oral contraception and parenteral hormonal contraceptives (patches, injectables and implants) that may be affected by enzyme-inducing drugs should only be used in combination with a barrier method. All males with partners of childbearing potential or whose partners are pregnant must use barrier contraception for the duration of dosing and for 5 months post-dosing.

Exclusion Criteria:

• Pregnant or breast feeding
• Pre-existing auto-immune conditions
• Medical conditions requiring systemic immunosuppression
• Previous treatment with an HDAC inhibitor or PD-1/PD-L1 inhibitor
• Other chemotherapy, radiotherapy, or investigational therapy within 4 weeks of the Screening /Baseline Assessment
• Unresolved clinically significant toxicity from a previous treatment
• History of recent active chronic inflammatory bowel disease and/or bowel obstruction
• Renal function: Serum creatinine > 1.5 x ULN, or creatinine clearance < 60mL/min (Cockcroft-Gault formula)
• Liver function: AST > 3.0 x ULN; OR total bilirubin > 1.5 x ULN
• Clinically significant myocardial infarction, severe/unstable angina pectoris, congestive heart failure NYHA Class III or IV, or pulmonary disease within 6 months
• Symptomatic brain metastasis, uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis
• Clinically significant active infection requiring antibiotic or antiretroviral therapy
• History of malignancy other than MSS CRC, unless there is the expectation that the malignancy has been cured, and tumour specific treatment for the malignancy has not been administered within the previous 5 years
• History of pneumonitis, immune hepatitis or myocarditis, or current uncontrolled thyroid disease
• Current positive serology for Hepatitis B or C virus
• History of any allergy to excipients of the Investigational Medicinal Products (sodium citrate dihydrate, sodium chloride, mannitol, pentetic acid, Polysorbate 80, sodium hydroxide, hydrochloric acid, hydroxypropyl methylcellulose)
• Receipt of any live vaccine 30 days or fewer prior to administration of first dose IMP
• Inability to comply with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CXD101 and Nivolumab combination; CXD101 will be presented as 10mg HPMC capsules and will be taken orally for 5 consecutive days repeated every three weeks on an outpatient basis.; Nivolumab will be presented as a 10 mg/mL solution in a single-dose vial, administered as iv infusion over 60 mins, repeated every two weeks.; CXD101 in combination with nivolumab will be administered in the Phase II component of the trial at doses determined in the Phase Ib component.

Drug: CXD101 in Combination With Nivolumab; HDAC inhibitor in combination with anti-PD-1 monoclonal antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Disease Control Rate (iDCR)	complete response [iCR], partial response [iPR], and stable disease [iSD] rate) after Seymour et al, 2017.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
20-week immune-related progression-free survival (PFS)	Progression-free survival will be measured from the date of first dose until death from any cause, with measurement cut-off at 20 weeks. Subjects who discontinue from treatment will classed as "censored" at the last timepoint when their PFS status was known. Subjects who discontinue from the study will be classed as "censored" at the time they discontinue. A Kaplan-Meier survival curve will be plotted and the 20-week PFS rate determined, with a 95% confidence interval.	20 weeks
Best Objective Response Rate	iCR + iPR / iCR + iPR + iSD + iPD x 100. The Objective Response Rate will be calculated as the combined percentage of subjects who have achieved as best response: complete response, or partial response.	6 months
Overall Survival (OS)	Overall Survival will be measured from the date of first dose until death from any cause. Subjects who discontinue from treatment will be followed up for survival but will be classed as "censored" at the last timepoint when their survival status was known. Subjects who discontinue from the study will be classed as "censored" at the time they discontinue. A Kaplan-Meier survival curve will be plotted for overall survival.	6 months
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment	AEs may be directly observed, evident in laboratory or diagnostic results, reported spontaneously by the subject, or by questioning the subject at each study visit. All subjects who complete screening, receive at least one dose of study medication and who have at least one safety assessment (including "death") will be in the Safety Set.	6 months

Collaborators and Investigators

• Sponsor: Celleron Therapeutics Ltd.
• Investigators: Principal Investigator: Rachel Kerr, MD, Department of Oncology, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2018
• Primary Completion (Anticipated): December 15, 2019
• Study Completion (Anticipated): June 15, 2020

Study Registration Dates

• First Submitted: June 19, 2019
• First Submitted That Met QC Criteria: June 20, 2019
• First Posted (Actual): June 21, 2019

Study Record Updates

• Last Update Posted (Actual): June 21, 2019
• Last Update Submitted That Met QC Criteria: June 20, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: CTL-101-023; 2017-004509-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No