A Safety Study of NUC-7738 in Patients With Advanced Solid Tumours or Lymphoma

Overview

This is a two-part, Phase I, dose-escalation study of NUC-7738 administered by intravenous infusion across two administration schedules. Part 1 is a dose-escalation study in patients with advanced solid tumours to assess the safety and tolerability of NUC-7738, in addition to establishing the recommended phase II dose (RP2D) and dose administration schedule of NUC-7738 for further exploration in Part 2 of the study. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of approximately 40 additional patients with advanced solid tumours and approximately 12 patients with lymphoma.

Full Title of Study: “A Two-part, Phase I, Open-label, Dose-escalation and Expansion Study to Assess the Safety, Pharmacokinetics and Clinical Activity of NUC-7738, a Nucleotide Analogue, in Patients With Advanced Solid Tumours or Lymphoma.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 2022

Interventions

  • Drug: NUC-7738
    • NUC-7738

Arms, Groups and Cohorts

  • Experimental: NUC-7738
    • NUC-7738 administered by intravenous infusion on a weekly or fortnightly schedule. In the weekly dosing schedule, NUC-7738 is administered on Days 1 and 8 of a 14-day cycle. In the fortnightly dosing schedule, NUC-7738 is administered on Day 1 of a 14-day cycle.

Clinical Trial Outcome Measures

Primary Measures

  • Number of patients with dose-limiting toxicities
    • Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered
    • Safety and tolerability of NUC-7738
  • Number of patients with treatment-emergent adverse events (CTCAE v5.0)
    • Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered
    • Safety and tolerability of NUC-7738
  • Number of patients with clinically significant laboratory changes (CTCAE v5.0)
    • Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered
    • Safety and tolerability of NUC-7738
  • Number of patients with changes in physical exam, vital signs, and serial electrocardiograms.
    • Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered
    • Safety and tolerability of NUC-7738
  • RP2D for NUC-7738 administered via weekly and fortnightly dosing schedules
    • Time Frame: Until completion of Part 1 (an average of 1 year)
    • Part 1 only

Secondary Measures

  • Plasma and/or peripheral blood mononuclear cell levels of NUC-7738 and its metabolites
    • Time Frame: Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (each cycle is 14 days)
    • Pharmacokinetics
  • Percentage change from baseline in tumour size
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): The percentage change in the sum of longest diameters of target lesions from baseline to Week 8. The best percentage change in the sum of longest diameters of target lesions from baseline to best on-treatment measurement
  • Objective response rate
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the number of patients achieving a confirmed response (complete response [CR] or partial response [PR])
  • Duration of response
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for CR or PR until the first date that recurrence or progressive disease (PD) is objectively documented (responders only)
  • Disease control rate
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response
  • Duration of stable disease
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or PD is objectively documented
  • Progression free survival
    • Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months)
    • Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from first dose of study treatment until the date of objective disease progression or death

Participating in This Clinical Trial

Inclusion Criteria

1. Provision of signed written informed consent 2. Histologically confirmed diagnosis of an advanced solid tumour (Part 1 and 2) or lymphoma (Part 2 only), which is not amenable to standard chemotherapy, is refractory to standard chemotherapy, or for which no standard chemotherapy exists 3. Age ≥18 years (no upper age limit) 4. Eastern Cooperative Oncology Group performance status of 0 or 1 5. Life expectancy of ≥12 weeks 6. Part 1 and Part 2: enrolment of patients with advanced solid tumours. Patients must have measurable disease as per RECIST v1.1 criteria and/or evaluable disease (evaluable: cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions, which do not fulfil RECIST v1.1 criteria for measurable disease) for solid tumours. 7. Part 2: enrolment of patients with lymphoma. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma. 8. Adequate bone marrow, liver, and renal function 9. Ability to comply with protocol requirements 10. Patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method of contraception, from the time of screening until 30 days after the last dose of study medication. 11. Willing to undergo biopsy of suitably accessible lesions. Patients who do not have easily accessible tumour for biopsy should not be put at undue risk for sample collection and these patients remain eligible for the study. Exclusion Criteria:

1. History of allergic reaction fo any of the components of NUC-7738 2. Symptomatic central nervous system or leptomeningeal metastases 3. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), immunotherapy, or exposure to another investigational agent within 28 days (for biological agents decision on washout period will be made on a case by base basis) of first administration of the IMP: 1. For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-7738 2. For hormone therapy within 14 days of first administration of NUC-7738 3. Corticosteroid treatment is allowed during the screening period but should be weaned to a dose of 10 mg prednisolone (or steroids equivalent) by Cycle 1 Day 1. 4. Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy and alopecia 5. Presence of any uncontrolled concomitant illness, serious illness, medical conditions, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with their participation in the study, or with the interpretation of results, including the following: 1. Congestive heart failure (New York Heart Association Class III or Class IV) 2. Myocardial infarction within 6 months of the first dose of study medication 3. Unstable or poorly controlled angina pectoris 4. Complete left bundle branch, bifasicular block or other clinically significant abnormal electrocardiogram finding 5. A history of or current risk factor for Torsades de Point (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome) 6. A history of, or current diagnosis of, interstitial pneumonitis or pulmonary fibrosis 6. Known human immunodeficiency virus positive or known active hepatitis B or C. Presence of an active bacterial or viral infection including Herpes zoster or chicken pox 7. Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location etc.) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures 8. Currently pregnant, lactating or breastfeeding 9. QTc interval >450 milliseconds for males and >470 milliseconds for females 10. Concomitant use of drugs known to prolong QT/QTc interval 11. Have received a live vaccination within four weeks of first planned dose of study medication.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • NuCana plc
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Elisabeth Oelmann, MD PhD, Study Director, NuCana plc
  • Overall Contact(s)
    • Bryn Dixon, +44 (0)131 357 1116, bryndixon@nucana.com

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