A Safety, Pharmacokinetic and Efficacy Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer Treatment

NCT03428958 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: NuTide:3022017-002062-53
• Study Type: interventional
• Target: 111
• Locations: 3 countries
• Sites: 10

Brief Summary

This is a three-part study of NUC-3373 administered by intravenous (IV) infusion across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (leucovorin, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). The primary objective is to identify a recommended dose and schedule for NUC-3373 when combined with these agents.

Conditions

Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Tumors; Neoplasms, Colorectal

Keywords

Relapsed metastatic adenocarcinoma of colon/rectum

Outcome Measures

Primary Outcomes (6)

• Percentage Change From Baseline in Tumour Size

  Efficacy (per RECIST v 1.1): defined as the best percentage change from baseline in tumour size (mm)

  Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)

• Disease Control Rate (DCR)

  Efficacy (per RECIST v 1.1): 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 until the end of study (up to 25 months)

• Duration of Stable Disease (DoSD)

  Efficacy (per RECIST v 1.1): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or progressive disease (PD) is objectively documented

  Assessed every 8 weeks following Day 1 until the end of study (up to 25 months)

• Progression Free Survival (PFS)

  Efficacy (per RECIST v 1.1): 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 until the end of study (up to 25 months)

• Overall Survival (OS)

  Efficacy: defined as the time from randomization until the date of death from any cause

  From the date of randomization until the date of death from any cause, until the end of study (up to 25 months)]

• Best Overall Response

  Best overall response to study treatment according to RECIST v1.1

  Assessed every 8 weeks from Day 1 until the end of study (up to 25 months)

Study Arms (15)

NUC-3373 + leucovorin (LV) every other week

EXPERIMENTAL

Arm 1a: NUC-3373 administered IV followed by a 2-week washout period. The next dose of NUC-3373 administered in combination with LV at 400 mg/m2. All subsequent doses of NUC-3373 administered in combination with LV every 2 weeks in 28-day cycles.

Drug: NUC-3373 + leucovorin

NUC-3373 every other week

EXPERIMENTAL

Arm 1b: LV 400 mg/m2 administered IV over 2 hours prior to NUC-3373 infusion followed by a 2-week washout period. Then, NUC-3373 administered IV every 2 weeks without LV in 28-day cycles.

Drug: NUC-3373

NUC-3373 + leucovorin (LV) weekly

EXPERIMENTAL

Arm 1c: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV weekly on Days 1, 8, 15 and 22 of 28-day cycles.

Drug: NUC-3373 + leucovorin

NUC-3373 + leucovorin (LV); combination chemotherapy ineligible

EXPERIMENTAL

Arm 1d: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV on Days 1, 8, 15 and 22 of 28-day cycles.

Drug: NUC-3373 + leucovorin

NUC-3373 + oxaliplatin weekly

EXPERIMENTAL

Arm 2a: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.

Drug: NUFOX

NUC-3373 + irinotecan weekly

EXPERIMENTAL

Arm 2b: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.

Drug: NUFIRI

NUC-3373 + oxaliplatin (NUFOX) expansion

EXPERIMENTAL

Arm 2c: At the completion of Arm 2a, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.

Drug: NUFOX

NUC-3373 + irinotecan (NUFIRI) expansion

EXPERIMENTAL

Arm 2d: At the completion of Arm 2b, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.

Drug: NUFIRI

NUFOX + bevacizumab weekly

EXPERIMENTAL

Arm 3a: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with bevacizumab. NUC-3373+LV will be administered weekly, oxaliplatin and bevacizumab will be administered every other week.

Drug: NUFOX + VEGF pathway inhibitor

NUFOX + bevacizumab every other week

EXPERIMENTAL

Arm 3b: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a will be combined with bevacizumab. NUC-3373+LV+oxaliplatin+bevacizumab will be administered every other week.

Drug: NUFOX + VEGF pathway inhibitor

NUFIRI + bevacizumab weekly

EXPERIMENTAL

Arm 3c: NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with bevacizumab. NUC-3373+LV will be administered weekly, irinotecan and bevacizumab will be administered every other week.

Drug: NUFIRI + VEGF pathway inhibitor

NUFIRI + bevacizumab every other week

EXPERIMENTAL

Arm 3d: NUC-3373, LV and irinotecan at dose levels used in Arm 2b will be combined with bevacizumab. NUC-3373+LV+irinotecan+bevacizumab will be administered every other week.

Drug: NUFIRI + VEGF pathway inhibitor

NUC-3373 + LV + bevacizumab; maintenance patients

EXPERIMENTAL

Arm 3e: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with bevacizumab (administered every other week).

Drug: NUC-3373 + bevacizumab

NUFOX + cetuximab

EXPERIMENTAL

Arm 3f: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2a may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or every other week, oxaliplatin will be administered every other week and cetuximab will be administered weekly.

Drug: NUFOX + EGFR inhibitor

NUFIRI + cetuximab

EXPERIMENTAL

Arm 3g: NUC-3373, LV and irinotecan at dose levels used in Arm 2b may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or every other week, irinotecan will be administered every other week and cetuximab will be administered weekly.

Drug: NUFIRI + EGFR inhibitor

Interventions

NUC-3373 + leucovorin DRUG

NUC-3373 + leucovorin

Also known as: folinic acid, levoleucovorin, Nucleotide analogue

NUC-3373 + leucovorin (LV) every other week; NUC-3373 + leucovorin (LV) weekly; NUC-3373 + leucovorin (LV); combination chemotherapy ineligible

NUC-3373 DRUG

NUC-3373

Also known as: Nucleotide analogue

NUC-3373 every other week

NUFOX DRUG

NUC-3373 + oxaliplatin

Also known as: Eloxatin, Nucleotide analogue

NUC-3373 + oxaliplatin (NUFOX) expansion; NUC-3373 + oxaliplatin weekly

NUFOX + VEGF pathway inhibitor DRUG

NUC-3373 + oxaliplatin + bevacizumab

Also known as: Eloxatin, Avastin, Nucleotide analogue

NUFOX + bevacizumab every other week; NUFOX + bevacizumab weekly

NUFOX + EGFR inhibitor DRUG

NUC-3373 + oxaliplatin + cetuximab/panitumumab

Also known as: Eloxatin, Erbitux, Nucleotide analogue, Vectibix

NUFOX + cetuximab

NUFIRI DRUG

NUC-3373 + irinotecan

Also known as: Campto, Camptosar, Nucleotide analogue

NUC-3373 + irinotecan (NUFIRI) expansion; NUC-3373 + irinotecan weekly

NUFIRI + VEGF pathway inhibitor DRUG

NUC-3373 + irinotecan + bevacizumab

Also known as: Campto, Camptosar, Avastin, Nucleotide analogue

NUFIRI + bevacizumab every other week; NUFIRI + bevacizumab weekly

NUFIRI + EGFR inhibitor DRUG

NUC-3373 + irinotecan + cetuximab/panitumumab

Also known as: Campto, Camptosar, Erbitux, Nucleotide analogue, Vectibix

NUFIRI + cetuximab

NUC-3373 + bevacizumab DRUG

NUC-3373 + bevacizumab

Also known as: Nucleotide analogue, Avastin

NUC-3373 + LV + bevacizumab; maintenance patients

Eligibility Criteria

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

You may qualify if:

• All patients
• Provision of written informed consent
• Have histological confirmation of CRC with evidence of locally advanced/unresectable or metastatic disease
• Age ≥18 years
• Life expectancy of ≥12 weeks
• ECOG Performance status 0 or 1
• Measurable disease as defined by RECIST v1.1
• Known RAS and BRAF status. Patients with wild-type KRAS tumours who are to be enrolled to a cohort that does not contain an EGFR pathway inhibitor (Arms 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d and 3e) must have received prior treatment with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations. Patients with BRAF V600E mutant tumours should have received prior treatment with encorafenib in combination with an EGFR inhibitor, unless this was not standard of care according to relevant region-specific treatment recommendations
• Adequate bone marrow function as defined by: ANC ≥1.5×10\^9/L, platelet count ≥100×10\^9/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL
• Adequate liver function as defined by serum total bilirubin ≤1.5×ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases present)
• Adequate renal function assessed as serum creatinine \<1.5×ULN or glomerular filtration rate ≥50 mL/min. This criterion does not apply to Arm 1d.
• Serum albumin ≥3 g/dL
• For the cohort in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs
• Ability to comply with protocol requirements
• Female patients of child-bearing potential must have a negative serum pregnancy test within 7 days prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy. Male patients and female 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.

You may not qualify if:

• All patients
• Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine
• Prior history of hypersensitivity or current contra-indications to any of the combination agents required for the study arm to which the patient is assigned
• History of allergic reactions attributed to the components of the NUC-3373 drug product formulation
• Symptomatic CNS or leptomeningeal metastases
• Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months
• Chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy \[e.g. for bone pain\]), immunotherapy or exposure to another investigational agent within 28 days (or five times half-life for a biological or molecular targeted agent or three times the half-life for an immunotherapy agent) of first receipt of study drug
• Residual toxicities from prior chemotherapy or radiotherapy, which have not regressed to Grade ≤1 severity (CTCAE v5.0) except for alopecia. In cohorts not containing oxaliplatin, residual Grade 2 neuropathy is allowed.
• History of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ of the cervix, surgically excised or potentially curatively treated ductal carcinoma in situ of the breast, or low grade prostate cancer or patients after prostatectomy not requiring treatment. Patients with previous invasive cancers are eligible if treatment was completed more than 3 years prior to initiating the current study treatment and there is no evidence of recurrence.
• Presence of active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster or chicken pox), known HIV positive or known active hepatitis B or C
• Presence of any uncontrolled concurrent serious illness, medical condition 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 the results
• Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location) 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
• Required concomitant use of drugs known to prolong QT/QTc interval

Sponsors & Collaborators

• NuCana plc: lead

Study Sites (10)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Seattle Cancer Center

Seattle, Washington, 98109-1023, United States

Location

Compass Oncology

Vancouver, Washington, 98684, United States

Location

Hopital Franco-Britannique

Levallois-Perret, 92300, France

Location

The Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, W1T 7HA, United Kingdom

Location

University of Oxford

Oxford, OX3 7LE, United Kingdom

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms

Interventions

Leucovorin; Levoleucovorin; Oxaliplatin; Bevacizumab; Cetuximab; Panitumumab; Irinotecan

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids

Results Point of Contact

• Title: Medical and Scientific Affairs Department
• Organization: NuCana plc

info@nucana.com

+44 131 357 1111

Study Officials

• Elisabeth Oelmann, MD PhD

  NuCana plc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: This is a three-part study of NUC-3373 administered by IV across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (LV, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). Part 1 will determine if NUC-3373 should be administered with LV. Part 2 consists of a dose escalation phase, to assess the safety/tolerability of different doses of NUC-3373 in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI), and an expansion phase, to assess weekly schedules of NUFOX and NUFIRI regimens selected in the escalation phase. Part 3 will assess the safety/efficacy of NUFOX and NUFIRI regimens administered in combination with bevacizumab, cetuximab or panitumumab. Additional patients may be enrolled in all parts to replace patients who withdraw prior to completing the 28-day safety evaluation period to complete the min number patients per cohort. Enrolment may be expanded at the DSMCs discretion.

Study Record Dates

• First Submitted: February 2, 2018
• First Posted: February 12, 2018
• Study Start: October 5, 2018
• Primary Completion: March 19, 2024
• Study Completion: March 21, 2024
• Last Updated: April 23, 2025
• Results First Posted: April 23, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (6); GB (3); FR (1)