Comparison of Cyclophosphamide and doxorubicin as a first line treatment in elderly patients with metastatic sarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Jun 2021 → ongoing

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PHRC

External identifiers

EU CT number

2024-510653-10-00

EudraCT number

2018-000542-20

ClinicalTrials.gov

NCT04757337

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

The primary objective is to investigate whether treatment with oral cyclophosphamide improves the outcome of elderly patients (≥65 years old) with advanced/metastatic STS, compared with doxorubicin in term of PFS.

Secondary objectives 5

1. Comparison of oral cyclophosphamide versus doxorubicin in terms of additional efficacy endpoints:  Overall survival (OS);  Best response under treatment;  Time until definitive deterioration (TUDD) of health-related quality of life (HRQoL);
2. Assessment of the toxicity profile of oral cyclophosphamide and doxorubicin, as per NCI CTCAE v5.0
3. Assessment of the prognostic value on efficacy (PFS, OS)
4. Assessment of the geriatric characteristics of the randomized population
5. Assessment of compliance to oral metronomic cyclophosphamide (arm B only)

Conditions and MedDRA coding

Advanced or metastatic soft tissue sarcoma (STS) in patients ≥65 years old

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trust person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent
2. Age ≥65 years (inclusions will be managed to ensure that at least 50% of the randomized patients are ≥75 years old)
3. Diagnosis of soft-tissue sarcoma histologically confirmed by RRePS (Réseau de Référence en Pathologie des Sarcomes et des Viscères)
4. Metastatic or locally advanced disease not amenable to surgery, radiation, or combined modality treatment with curative intent. Palliative radiation therapy is permitted only if direct on nontarget lesion
5. Documentation of disease progression within the last 6 months before randomization
6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT-scan as defined by response evaluation criteria in solid tumors (RECIST) v1.1
7. Life expectancy of at least 6 months
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2
9. Patient suitable to receive doxorubicin as assessed by the investigator
10. Left ventricular ejection fraction (LVEF) value by echocardiogram or Multiple gated acquisition scanning (MUGA) ≥55%
11. Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: a. Absolute neutrophil count (ANC) ≥1,500/mm3 b. Platelets ≥100,000/mm3 c. Hemoglobin ≥9.0 g/dL d. Serum creatinine ≤2 x upper limit of normal (ULN) e. Glomerular filtration rate (GFR) ≥50 ml/min/1.73m2 (calculated with MDRD) f. AST and ALT ≤2.5 x ULN (≤5.0 × ULN for patients with liver involvement of their cancer ) g. Total bilirubin ≤1.5 X ULN h. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN with liver involvement of their cancer) i. serum albumin > 25 g/L j. Prothrombin time (PT)/International normalized ratio (INR) ≤1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until PT/INR is stable based on a measurement that is pre-dose as defined by the local standard of care.
12. Male patients must agree to use adequate contraception for the duration of trial participation and up to 6 months after completing treatment/therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care
13. Patients must be affiliated to a Social Security System (or equivalent)
14. Patient is willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures including follow-up

Exclusion criteria 22

1. Previous systemic treatment for advance or metastatic sarcoma
2. Previous neoadjuvant or adjuvant anthracycline treatment for localized sarcoma
3. Soft-tissue sarcoma with the following histological subtypes: dermatofibrosarcoma protuberans, desmoid tumor, alveolar or embryonal rhabdomyosarcoma, Desmoplastic small round cell tumor, Kaposi Sarcoma, Gastro-Intestinal stromal tumor, Peripheral neuroectodermal tumors
4. Primary bone sarcoma (including osteosarcoma, Ewing tumor, chondrosarcoma, and chordoma)
5. Symptomatic or known central nervous system (CNS) metastases
6. Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator and history of radiotherapy mediastinal in the last five years
7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before Day 1 of treatment
8. Active cardio vascular disease including any of the following: Congestive heart failure (New York Heart Association [NYHA] ≥Class 2), unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), acute inflammatory cardiopathy, severe arythmia, high risk of bleeding, cerebrovascular accident within the last 6 months
9. Uncontrolled grade >2 hypertension. (Systolic blood pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite optimal medical management)
10. Ongoing infection ≥Grade 2 according to NCI Common Terminology Criteria for Adverse Events version (CTCAE v. 5.0)
11. Known history of human immunodeficiency virus (HIV) infection
12. Known history of chronic hepatitis B or C
13. History of organ allograft
14. Pre-existing acute hemorrhagic cystitis, urinary tract obstruction, acute urinary tract infection
15. Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
16. Substance abuse, medical condition, that may interfere with the patient's participation in the study or evaluation of the study results
17. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
18. Inability to swallow oral medications, any malabsorption condition.
19. Persons deprived of their liberty or under protective custody or guardianship
20. Participation in another therapeutic trial within the 30 days prior to randomization and during the study
21. Patients having received live attenuated vaccine therapy used for prevention of diseases as influenza, chickenpox, zoster, measles, mumps, rubella, tuberculosis, rotavirus or yellow fever within 4 weeks of the first dose of study drug. These vaccinations are not permitted during the study up to 6 months after the last treatment
22. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is progression-free survival (PFS). PFS is defined as the time interval between the date of randomization and the date of progression (according to RECIST v1.1) or death, whichever occurs first.

Secondary endpoints 7

1. OS is defined as the time interval between the date of randomization and the date of death of any cause.
2. Best response under treatment: Best response (as per RECIST v1.1) recorded from randomization's date until the end of treatment.Each patient will be assigned one of the following categories: complete response,partial response,stable disease,disease progression, or unevaluable for response (specify reasons,e.g. early death,malignant disease;toxicity;tumor assessment not repeated/incomplete;other).Responses will have to be confirmed at least 4 weeks after evaluation to exclude measurement errors
3. Time until definitive deterioration (TUDD) of Health-related quality of life (HRQoL) is defined as the time interval between the date of randomization and the date of first deterioration of at least 10 points of the HRQoL score compared to baseline score, without any subsequent improvement as detailed further in Bonnetain et al. HRQoL will be assessed through Quality of life questionnaire - Core 30 (QLQ-C30) and Quality of life questionnaire – Elderly cancer patients (QLQ-ELD14).
4. Toxicity: Adverse events will be graded according to the CTCAE v5.0.
5. Identification of prognostic factors of PFS and OS.
6. Geriatric condition. Based on the recent work of the DIALOG task force for definition of G-CODE for clinical oncology research, geriatric data will be collected as follows :  1. Social environment: 2 questions -  2. Functional status: ADL and 4-IADL 3. Mobility: Time Get Up and Go test (TUG)  4. Nutritional Status: Weight loss during the last 6 months and BMI. 5. Cognitive status: Mini-Cog  6. Depressive mood: Mini-GDS  7. Comorbidities:
7. Compliance to oral metronomic cyclophosphamide (arm B only): compliance will be assessed based on data reported by the patients (patient diary).

Investigational products

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

Test 1

Comparator 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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