Digoxin for the Reinduction or Radioiodine Uptake in Metastatic or Locally Advanced Non-medullary Thyroid Cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Radboud University Medical Center

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Nov 2022 → 21 Jun 2023

Decision date (initial)

2022-08-23

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

KWF Dutch Cancer Society

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective is to study the beneficial effects of digoxin in patients with non-medullary thyroid carcinoma (NMTC) with locally advanced or metastatic disease with insufficient accumulation of RaI on reinduction of RaI uptake.

Secondary objectives 2

1. The secondary objective is to study the beneficial effects of RaI therapy on tumor progression after reinduction of RaI uptake with digoxin and to assess safety of digoxin treatment.
2. An explorative objective is to evaluate alterations in responding and non-responding tumor lesions after re-differentiation treatment on transcriptional and translational level and assessment of autophagy activity in primary tumors and target lesions if material is available.

Conditions and MedDRA coding

Non-medullary thyroid Carconoma (NMTC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Being diagnosed with NMTC.
2. Being aged ≥18 years.
3. Having undergone total thyroidectomy and at least 1 treatment with RaI.
4. The presence of local or metastatic disease, radiologically proven. A minimum of 1 target lesion (minimum of 1.0 cm for soft tissue and 1.5 cm for lymph nodes) must be present.
5. RaI refractory disease: at least one lesion (target lesion, needs to fulfil the above-mentioned criteria) without therapeutic relevant RaI uptake at previous post-therapeutic RaI scintigraphy and/or negative diagnostic RaI scan.
6. Target lesion must not be eligible for local treatments (radiotherapy, radiofrequency ablation, etc.). In case of multiple lesions, local treatment is allowed, but these lesions are not considered target lesions.

Exclusion criteria 16

1. Contraindications for digoxin: Creatinine clearance < 50 ml/min and/or active kidney disease; Cardiac arrhythmias (history of arrhythmias and arrhythmias at ECG); Electrolyte disorders
2. Pregnancy, lactating or breast-feeding women. Negative pregnancy test is mandatory within 7 days prior to starting the study premenopausal women. Women of non-childbearing potential may be included without pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those, which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
3. Having undergone a CT-scan with contrast agent within the last three months (this would reduce the iodide uptake).
4. Prior therapy with 131I <6 months prior to initiation of therapy on this protocol. A diagnostic study using <400 MBq of 131I is not considered 131I-therapy.
5. External beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol. (Previous treatment with radiation for any indication is allowed if the investigator judges that the previous radiation does not significantly compromise patient safety on this protocol).
6. Chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is not allowed < 4 weeks prior to the initiation of therapy on this protocol.
7. Eastern Cooperative Oncology Group (ECOG) score >2.
8. Use of other investigational drugs within 4 weeks preceding the first dose of drug treatment during this study.
9. A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the investigational drug.
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
11. Unwillingness or inability to comply with study and follow-up procedures.
12. Condition of patient which is critical to participate in this study in the discretion of the PI.
13. Rapidly progressive disease in which urgent start with systemic therapy is required.
14. Concomitant drugs that interfere with digoxin metabolism such as P-glycoprotein inductors or inhibitors, including but not limited to penicillamin, sufasalazin, tipranavir, amiodaron, diltiazem, itraconazol, ketoconazol, kinidin, lapatinib, propafenon, vemurafenib, verapamil, azitromycin, claritromycin, erythromycin, roxitromycin, chloroquin, ciclosporin, anti HCV drugs, anti-HIV drugs, hydroxychloroquine.
15. Patients who do not have normal organ and bone marrow function as defined below: Absolute neutrophil count (ANC) >1.5x109/L; Hemoglobin ≥ 9 g/dL; Platelets ≥ 100 x 109/L.
16. Other active malignancies other than basal cell carcinoma. Malignancies that have been in complete remission for >2 years are not considered active malignancies.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The number and percentage of subjects in whom there is reinduction of RaI uptake in RaI refractory target lesions. This will be assessed using RaI scintigraphy.

Secondary endpoints 5

1. The proportion of subjects with a favorable response to RaI treatment after 6 months, according to RECIST criteria.
2. Biochemical response to RaI treatment after 6 months, measured by thyroglobulin (TG).
3. Toxicity assessment using CTAE criteria v4.0.
4. Quality of life using EORTC QLQ-C30.
5. o Correlations between molecular pattern in pre-treatment biopsies (if available) and other study endpoints.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Radboud University Medical Center

Sponsor organisation

Stichting Radboud University Medical Center

Address

Geert Grooteplein Zuid 10

City

Nijmegen

Postcode

6525 GA

Country

Netherlands

Scientific contact point

Organisation

Stichting Radboud University Medical Center

Contact name

R.T. Netea-Maier, MD, PhD

Public contact point

Organisation

Stichting Radboud University Medical Center

Contact name

Drs. P. van Houten

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications