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

Study Overview
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Brief Summary
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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 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. In addition, 12 patients with lymphoma (with potential expansion to a total of 25 patients) may be enrolled to receive NUC-7738 monotherapy.

Official Title
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A Phase I/II, 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 and Lymphoma

Conditions
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Advanced Cancer, Lymphoma, Solid Tumor

Intervention / Treatment
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* Drug: NUC-7738
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 cutaneous melanoma with measurable disease as per RECIST v1.1 criteria. Must have progressed on ≤2 prior lines of therapy for advanced/metastatic cutaneous melanoma, that may have included 1 prior line of an immunotherapy-containing regimen (either monotherapy or in combination with chemotherapy). Patients who have not progressed but where addition of NUC 7738 to standard pembrolizumab monotherapy may be appropriate are also eligible. 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 Phase II 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. Patient must be willing to undergo a new tumour biopsy at Screening and during therapy on the study. Biopsies are mandatory for patient inclusion, except where taking a biopsy would be associated with unacceptable clinical risk due to the location of the disease. Such patients may be discussed on a case-by-case basis with the study Medical Monitor to determine their eligibility. A prior (archival) biopsy that is less than 3 months old may be substituted for a fresh tumour biopsy at Screening with agreement from the Medical Monitor. 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. Exclusion Criteria: The following exclusion criteria apply to all patients. Please also refer to additional exclusion criteria for the NUC-7738 + pembrolizumab cohort below. History of allergic reaction fo any of the components of NUC-7738 Symptomatic central nervous system or leptomeningeal metastases 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. Phase II only; prior treatment with CAR-T cells 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 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 Currently pregnant, lactating or breastfeeding QTc interval >450 milliseconds for males and >470 milliseconds for females Concomitant use of drugs known to prolong QT/QTc interval Concomitant use of strong CYP3A4 inducers or strong CYP3A4 inhibitors. The use of strong CYP3A4 inducers within 2 weeks of first receipt of study drug or the use of strong CYP3A4 inhibitors within 1 week of first receipt of study drug is also excluded. Have received a live vaccination within four weeks of first planned dose of study medication. NUC-7738 + pembrolizumab cohort only Any history of hypersensitivity or current contra-indication to the components of pembrolizumab (L-histidine, polysorbate 80, sucrose, sodium hydroxide, hydrochloric acid) Current contra-indication to immunotherapy with checkpoint inhibitors. Systemic steroid therapy or any immunosuppressive therapy (≥10 mg/day prednisone or equivalent). Known neutralising antibodies against checkpoint inhibitors. Patients previously exposed to checkpoint inhibitors who are not adequately treated for skin rash or have no replacement therapy for endocrinopathies. Any prior toxicity attributed to checkpoint inhibitors that resulted in discontinuation of therapy Active autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease or any condition that requires systemic steroids.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NUC-7738<br>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<br>* NUC-7738<br>* Other names: Nucleotide Analogue;|
| Experimental: NUC-7738 + pembrolizumab<br>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<br>* NUC-7738<br>* Other names: Nucleotide Analogue;Drug: Pembrolizumab<br>* Pembrolizumab<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Phase I: Clearance 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 II: Plasma concentration of NUC-7738 at end of infusion (Cinf) |  | 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 II: Maximum observed plasma concentration (Cmax) 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 II: Area under the plasma concentration-time curve (AUC) 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 II: 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 II: 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) | 
| Phase II: Clearance 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) | 
| Percentage change from baseline in tumour size | Phase I: 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 | 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) | 
| ORR | Phase I: 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]) | 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) | 
| DoR | Phase I: 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) | 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) | 
| DCR | Phase I: 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 | 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) | 
| DoSD | Phase I: 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 | 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) | 
| PFS | Phase I: 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 | 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) | 
| Number of patients with treatment-emergent adverse events (CTCAE v5.0) | Phase II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma | 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 II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma | 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 II: Safety and tolerability of NUC-7738 as a single-agent or in combination with pembrolizumab in patients with advanced solid tumours and lymphoma | From the date of consent until 30 days after the last dose of NUC-7738 administered | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors, Lymphoma, Cordycepin, Pembrolizumab