Cancer Drug Derived From Himalayan 'Caterpillar Fungus' Smashes Early Clinical Trial

A new kind of chemotherapy derived from a molecule found in a Himalayan fungus has been revealed as a potent anti-cancer agent, and may in the future provide a new treatment option for patients with cancer.

NUC-7738, synthesized by researchers at the University of Oxford in partnership with UK-based biopharmaceutical company NuCana, is still in the experimental testing stages and isn't available as an anti-cancer medication yet – but newly reported clinical trial results bode well for the drug candidate.

The active ingredient in NUC-7738 is called cordycepin, which was first found in the parasitic fungus species Ophiocordyceps sinensis (also known as caterpillar fungus because it kills and mummifies moth larva), used as a herbal remedy in traditional Chinese medicine for centuries.

Cordycepin, also known as 3'-deoxyadenosine (or 3'-dA), is a naturally occurring nucleoside analogue, reported to offer a range of anti-cancer, anti-oxidant, and anti-inflammatory effects, which goes some way to explaining why the fungus is sometimes called the world's most valuable parasite.

Naturally occurring cordycepin extracted from O. sinensis does have its drawbacks, however, including that it is broken down quickly in the bloodstream – with a half-life of 1.6 minutes in plasma – by the enzyme adenosine deaminase, or ADA. It also shows poor uptake into cells, meaning the molecule's actual potency against tumor cells in the body is greatly diminished.

To amplify cordycepin's potential as an anti-cancer agent, NUC-7738 makes use of a number of engineered advantages, allowing it to enter cells independently of nucleoside transporters, such as Human Equilibrative Nucleoside Transporter 1 (hENT1).

Unlike naturally occurring cordycepin, NUC-7738 doesn't rely on hENT1 to gain access to cells, and other tweaks to the molecule mean it's pre-activated (bypassing the need for the enzyme adenosine kinase), and is also resistant to breaking down in the bloodstream, with built-in protection against ADA.

According to a new study on NUC-7738, these changes make the drug candidate's anti-cancer properties up to 40 times more potent than cordycepin when tested against a range of human cancer cell lines.

Moreover, early results from the first in-human clinical trial of NUC-7738 appear to be positive so far too. The Phase 1 trial, which began in 2019 and is still ongoing, has so far involved 28 patients with advanced tumors that were resistant to conventional treatment.

So far, weekly escalating doses of NUC-7738 given to this cohort have been tolerated well by the patients, who have shown "encouraging signals of anti-tumor activity and prolonged disease stabilization", the researchers report in their paper.

"These findings provide proof of concept that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and support the further clinical evaluation of NUC-7738 as a novel cancer treatment."

While it's certainly a promising start, it will still be some time before NUC-7738 becomes available to patients outside the trial.

Planning is currently underway for Phase 2 of the trial, once the safety of the drug has been more thoroughly demonstrated, and once the recommended regimen for Phase 2 patients has been identified.

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A Safety Study of NUC-7738 in Patients With Advanced Solid Tumours or Lymphoma
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT03829254
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : June 8, 2021
See Contacts and Locations
Sponsor:
NuCana plc
Information provided by (Responsible Party):
NuCana plc

Study DetailsTabular ViewNo Results PostedDisclaimerHow to Read a Study Record
Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Cancer
Lymphoma
Solid Tumor
Drug: NUC-7738
Phase 1

Study Design
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Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 94 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : June 17, 2019
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022
Resource links provided by the National Library of Medicine
MedlinePlus related topics: Lymphoma
Genetic and Rare Diseases Information Center resources: Lymphosarcoma
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
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.
Drug: NUC-7738
NUC-7738
Other Name: Nucleotide Analogue

Outcome Measures
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Primary Outcome 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 Outcome 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

Eligibility Criteria
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Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:

Provision of signed written informed consent
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
Age ≥18 years (no upper age limit)
Eastern Cooperative Oncology Group performance status of 0 or 1
Life expectancy of ≥12 weeks
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.
Part 2: enrolment of patients with lymphoma. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.
Adequate bone marrow, liver, and renal function
Ability to comply with protocol requirements
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.
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:

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.
Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy and alopecia
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, bifasicular 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
Have received a live vaccination within four weeks of first planned dose of study medication.
Contacts and Locations
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Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03829254

Contacts
Contact: Bryn Dixon +44 (0)131 357 1116 bryndixon@nucana.com

Locations
United Kingdom
University of Edinburgh Recruiting
Edinburgh, United Kingdom, EH4 2XR
Contact: Ewa Kondarewicz
Freeman Hospital Recruiting
Newcastle, United Kingdom, NE7 7DN
Contact: Jennifer Thompson
University of Oxford Recruiting
Oxford, United Kingdom, OX3 7DQ
Contact: Mary Lomas
Sponsors and Collaborators
NuCana plc
Investigators
Study Director: Elisabeth Oelmann, MD PhD NuCana plc
More Information
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Responsible Party: NuCana plc
ClinicalTrials.gov Identifier: NCT03829254 History of Changes
Other Study ID Numbers: NuTide:701
2018-003417-17 ( EudraCT Number )
First Posted: February 4, 2019 Key Record Dates
Last Update Posted: June 8, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NuCana plc:
Solid tumors
Lymphoma
Cordycepin
Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

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