A Safety, Pharmacokinetic and Clinical Activity Study of NUC-7738 in Patients With Advanced Solid Tumours and Lymphoma

NCT03829254 | Recruiting Phase 1 DMC

• 2 other identifiers: NuTide:7012018-003417-17
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 9

Brief Summary

This is a Phase I/II, dose-escalation and expansion study of NUC-7738 administered by intravenous infusion as a monotherapy and in combination with pembrolizumab. In Phase I, NUC-7738 monotherapy is evaluated across two administration schedules (weekly or fortnightly) in a dose-escalation design in patients with advanced solid tumours. The main objectives are to assess the safety and tolerability of NUC-7738, in addition to establishing the Maximum Tolerated Dose (MTD) and dose administration schedule of NUC-7738 for further exploration in the Phase II part of the study. In Phase II, the selected dose and designated dosing schedule will be further evaluated in dose-confirmation expansion cohorts enrolling a total of approximately 40 additional patients with advanced solid tumours. Based on emerging data, approximately 6 patients with cutaneous melanoma will be enrolled to these expansion cohorts and will receive NUC-7738 monotherapy. A further cohort will assess NUC-7738 in combination with pembrolizumab in approximately 6-12 patients with cutaneous melanoma. Based on efficacy signals observed in the initial melanoma combination cohort, a further expansion cohort will be initiated to expand to a total of 40 patients to allow a powered analysis. In addition, 12 patients with lymphoma (with potential expansion to a total of 25 patients) may be enrolled to receive NUC-7738 monotherapy.

Conditions

Advanced Cancer; Lymphoma; Solid Tumor; Melanoma

Keywords

Solid tumors; Lymphoma; Cordycepin; Pembrolizumab; Melanoma

Outcome Measures

Primary Outcomes (11)

• Number of patients with dose-limiting toxicities

  Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours

  From the date of consent until 30 days after the last dose of NUC-7738 administered

• Number of patients with treatment-emergent adverse events (CTCAE v5.0)

  Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours

  From the date of consent until 30 days after the last dose of NUC-7738 administered

• Number of patients with clinically significant laboratory changes (CTCAE v5.0)

  Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours

  From the date of consent until 30 days after the last dose of NUC-7738 administered

• Number of patients with changes in physical exam, vital signs, and serial electrocardiograms.

  Phase I: Safety and tolerability of NUC-7738 in patients with advanced solid tumours

  From the date of consent until 30 days after the last dose of NUC-7738 administered

• MTD for NUC-7738 administered via weekly and fortnightly dosing schedules in patients with advanced solid tumours

  Phase I

  Until completion of Phase I (an average of 1 year)

• Percentage change from baseline in tumour size

  Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007)

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

• Objective response rate (ORR)

  Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the number of patients achieving a confirmed response (complete response \[CR\] or partial response \[PR\])

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

• Duration of response (DoR)

  Phase II: Efficacy (per RECIST v 1.1, iRECIST 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)

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

• Disease control rate (DCR)

  Phase II: Efficacy (per RECIST v 1.1, iRECIST 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

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

• Duration of stable disease (DoSD)

  Phase II: Efficacy (per RECIST v 1.1, iRECIST 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

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

• Progression free survival (PFS)

  Phase II: Efficacy (per RECIST v 1.1, iRECIST or Cheson et al, 2007): defined as the time from first dose of study treatment until the date of objective disease progression or death

  Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days) in single-agent cohorts and Cycle 8 in combination cohorts (each cycle is 21 days), moving to every 12 weeks until the end of study (up to 22 months)

Secondary Outcomes (21)

• Phase I: Plasma concentration of NUC-7738 at end of infusion (Cinf)

  Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).

• Phase I: Maximum observed plasma concentration (Cmax) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738

  Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).

• Phase I: Area under the plasma concentration-time curve (AUC) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738

  Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (cycle: 14 days).

• Phase I: Elimination half-life (t½) of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738

  Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)

• Phase I: Volume of distribution of NUC-7738, 3'-dA, 3'-deoxyinosine (3'-dI) and alanine phosphate metabolite of NUC-7738

  Single-agent cohorts: Samples collected on Days 1, 2 and 3 of each dose level (cycle: 14 days). Combination cohorts: Samples collected on Days 1, 2, and 3 of Cycle 1 and on Day 1 of the dose escalation step (cycle: 21 days)

Study Arms (2)

NUC-7738

EXPERIMENTAL

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.

Drug: NUC-7738

NUC-7738 + pembrolizumab

EXPERIMENTAL

NUC-7738 administered by intravenous infusion on a weekly schedule on Days 1, 8 and 15 of a 21-day cycle. Pembrolizumab administered by intravenous infusion every 3 weeks on Day 1 of a 21-day cycle.

Drug: NUC-7738; Drug: Pembrolizumab

Interventions

NUC-7738 DRUG

NUC-7738

Also known as: Nucleotide Analogue

NUC-7738; NUC-7738 + pembrolizumab

Pembrolizumab DRUG

Pembrolizumab

Also known as: Keytruda

NUC-7738 + pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed written informed consent.
• Solid tumour cohorts only (Phase I and Phase II; excluding NUC-7738 + pembrolizumab cohort): Histologically confirmed diagnosis of an advanced solid tumour with 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.
• NUC-7738 + pembrolizumab cohort only (Phase II): Histologically confirmed diagnosis of metastatic cutaneous melanoma with measurable disease as per RECIST v1.1 criteria. Must have progressed on ≤2 prior lines of therapy for advanced/metastatic disease. In addition, patients may have been treated in the neoadjuvant/adjuvant setting. At least one prior line must have included a PD-1/PD-L1-containing regimen (either monotherapy or in combination) for which they progressed on.
• Lymphoma cohort only (Phase II): Relapsed refractory lymphoma (high grade and low grade B-NHL, Hodgkin's Lymphoma and T-cell lymphomas), which is not amenable to standard of care, is refractory to standard of care or for which no standard of care exists. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.
• For solid tumours in single-agent Phase II cohorts only: patients should have received no more than 3 prior lines of treatment for metastatic disease.
• Age ≥18 years (no upper age limit).
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Life expectancy of ≥12 weeks.
• Adequate bone marrow, liver, and renal function.
• Ability to comply with protocol requirements.
• Female patients of child-bearing potential must have a negative serum pregnancy test within 3 days prior to the first NUC-7738 administration. All patients of child-bearing potential must agree to practice true abstinence or to use two forms of contraception, one of which must be a highly effective method of contraception, from the time of screening until 6 months after the last dose of study medication.
• Patients must have been advised to take measures to avoid or minimise exposure of the skin and eyes to UV light, including avoiding sunbathing and visits to the solarium, for the duration of study participation and for a period of 4 weeks following the last dose of study medication.

You may not qualify if:

• History of allergic reaction fo any of the components of NUC-7738.
• Central nervous system or leptomeningeal metastases. Patients with brain metastases are eligible if they have no ongoing neurological symptoms, have not received corticosteroids within 7 days prior to enrolment, and show radiographic stability for at least 2 weeks.
• 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:
• For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-7738
• For hormone therapy within 14 days of first administration of NUC-7738
• 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.
• Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy, ototoxicity and alopecia (which are excluded if ≥Grade 3).
• 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:
• Congestive heart failure (New York Heart Association Class III or Class IV).
• Myocardial infarction within 6 months of the first dose of study medication.
• Unstable or poorly controlled angina pectoris.
• Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram finding.
• A history of or current risk factor for Torsades de Point (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome).
• A history of, or current diagnosis of, interstitial pneumonitis or pulmonary fibrosis.
• 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.

Sponsors & Collaborators

• NuCana plc: lead

Study Sites (9)

Cambridge University Hospitals NHS Foundation Trust (Addenbrookes Hospital)

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

Edinburgh Cancer Centre, Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

RECRUITING

The Beatson West of Scotland Cancer Centre

Glasgow, G12 0TN, United Kingdom

RECRUITING

University College London Hospital

London, NW1 2PG, United Kingdom

RECRUITING

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

RECRUITING

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

RECRUITING

Freeman Hospital

Newcastle, NE7 7DN, United Kingdom

RECRUITING

Oxford University Hospitals NHS Foundation Trust

Oxford, OX3 9DU, United Kingdom

RECRUITING

Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital

Preston, PR2 9HT, United Kingdom

RECRUITING

MeSH Terms

Conditions

Lymphoma; Melanoma

Interventions

NUC-7738; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Central Study Contacts

NuTide:701 Project Manager

CONTACT

+44 (0)131 357 1111; NuTide701@nucana.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2019
• First Posted: February 4, 2019
• Study Start: June 17, 2019
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: January 12, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (9)