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Recurrent Endometrial CancerPhase 1/2ENDOLANCT02755844

Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients

A Phase 1/2 study testing Olaparib, metformin and metronomic cyclophosphamide in people with Recurrent Endometrial Cancer, run by Hospices Civils de Lyon at 6 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Read more about this study

Who is it for?
Ages 18 to 81 years, women only
Conditions the study is for
Recurrent Endometrial Cancer
What is being tested?
Olaparib, metformin and metronomic cyclophosphamide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
6 sitesFrance
Study dates
23 Sep 2016to Jun 2020
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 81 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Woman older than 18 years and younger than 81 year old
  • Patients with histologically and/or cytologically documented endometrial carcinoma (type I or type II), recurrent after platinum-based chemotherapy.
  • Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Archival tumor tissue available, or tumor lesion biopsy feasible
  • There is no limitation to prior number of therapies
  • Patients who have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
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  • Patients with adequate bone marrow function
  • Absolute neutrophile count ≥ 1.5 x 10 9 /L
  • Platelet count ≥ 100 x 10 9 /L
  • Haemoglobin ≥ 9 g/dL
  • Patients with adequate renal function :
  • Calculated creatinine clearance, using the MDRD formula, according to the standardized IDMS method (http://www.sfndt.org/sn/eservice/calcul/eDFG.htm by ticking IDMS standardized measurement).>= 60 ml/min
  • Patients with adequate hepatic function
  • Serum total bilirubin < 1.25 x upper normal limit (UNL) and aspartate aminotransferase (AST)/Alanine Amino transferase (ALT) ≤ 2.5 X UNL (≤ 5 X UNL for patients with liver metastases)
  • Patients must have a life expectancy ≥ 16 weeks
  • Female patients who are of childbearing potential: evidence of non-childbearing status, practicing practicing two medically acceptable methods of birth control since consent signature during the study and 12 months after the end of treatment
  • Patients who gave its written informed consent to participate to the study
  • Patients affiliated to a social insurance regime

Who cannot join

  • Illness, incompatible with metformin treatment, in particular those associated with a risk of hypoperfusion or hypoxia (not limited to): acute or chronic renal failure (creatinine clearance < 60 ml/min, using the MDRD formula according to the standardized IDMS method); lactic ketoacidosis; septic shock; congestive heart failure; respiratory distress; liver failure; chronic alcoholism; uncontrolled seizures; age > 80 years; allergy/hypersensitivity to metformin.
  • Previous treatment with cyclophosphamide; or allergy/hypersensitivity to cyclophosphamide or one of its excipients or one of its metabolits.
  • Illness incompatible with cyclophosphamide treatment: pre-existing hemorrhagic cystitis and urinary tract obstruction
  • Any previous treatment with a poly-adenosine diphosphate ribose (ADP) ribose polymerase (PARP) inhibitor, including olaparib.
  • Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
  • Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment. The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug.
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  • Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin boceprevir, telaprevir and nelfinavir and inducers such phenobarbital, phenytoin, carbamazepine, rifampicin.
  • Persistent toxicities (>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy.
  • Treatment with other investigational agents.
  • Bowel occlusive syndrome or other gastro-intestinal disorder that does not allow oral medication such as malabsorption.
  • Female patients who are pregnant or lactating, Active infection to HIV, hepatitis B or C, or have other forms of hepatitis or cirrhosis.
  • Symptomatic uncontrolled brain metastases. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.
  • Major surgery within 14 days of starting study treatment
  • Patients must have recovered from any effects of any major surgery.
  • Resting ECG with corrected QT interval (QTc) > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
  • Concomitant treatment with vitamin K antagonists
  • Patients under guardianship.
  • A diabetic patient may be included in the study. In that case:
  • If the patient is treated with metformin: Keep metformin at the usual dosage. There will be no prescription or dispensation in the study.
  • If the patient is being treated with another medicine (ex Stagid): Take the advice of a diabetologist or the referring physician for the patient's diabetes for the continuation of the same treatment and the addition of metformin to 500 mg/day.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

France6 sites

  • Service d'Oncologie Médicale, Centre François Baclesse

    Caen, 14076

  • Département de Cancérologie Cervico-Faciale et Thoracique, Centre Oscar Lambret

    Lille, 59000

  • Département d'Oncologie Médicale, Centre Antoine Lacassagne

    Nice, 06189

  • Service d'Oncologie Médicale, Institut Curie

    Paris, 75248

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, 69495

  • Comité Gynécologique, Institut Gustave Roussy

    Villejuif, 94800

Other trials in France

About this study

Official title: A Phase I/II Trial to Assess the Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Recurrent Advanced/Metastatic Endometrial Cancer Patients

Endometrial cancer ranks 11th in terms of incidence (7275 / year) and mortality (2025 deaths/ year). The 5-year overall survivals of patients at diagnosis with locally advanced and metastatic carcinomas are about 50% and 15% respectively. Beyond first line treatment with platinum-based chemotherapy, there is lack of effective drug in this disease, which explains the poor prognosis of patients.

The prognosis of metastatic endometrial cancer patients is poor, and few drugs have been shown to be effective beyond first chemotherapy line.

Read more

Endometrial carcinomas are characterized by frequent alterations of PI3K-AKT-mTor; IGF1R and of DNA repair pathways. Phosphatase and tensin homologue (PTEN)-phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTor) and DNA repair pathways interact, and inhibition of PI3K-AKT-mTor signaling pathway may alter DNA damage repair.

Metronomic cyclophosphamide regimen may increase the anti-proliferative effects of olaparib because it is an alkylating agent, and it exerts anti-angiogenic effects, with a favorable toxicity profile.

Metformin may increase the anti-proliferative effects of olaparib because it downregulates IGF1R and PI3K-AKT-mTor pathways, with no additive toxicity.

Being tested
Olaparib, metformin, metronomic cyclophosphamide
Keywords
endometrial carcinomas, metronomic cyclophosphamide, metformin, olaparib, dose-escalation study
Medical subject headings
Endometrial Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OlaparibDrug

    Olaparib tablet dose will be dose-escalated on 4 dose levels , guided by a continual reassessment method (CRM).

    One cycle will be 28 days (4 weeks) in duration, except for cycle 1 which will be 6 weeks.

  • metforminDrug

    From week 3 metformin will be gradually escalated from 500 mg/day to 1500 mg/day with weekly 500 mg dose escalation levels

  • metronomic cyclophosphamideDrug

    from week 2 Metronomic cyclophosphamide will be given continuously on an oral daily basis at 50 mg qd

Study groups in NCT02755844
Study groupRoleWhat they receive
Olaparib, metformin and metronomic cyclophosphamideExperimentalPhase 1: Dose escalation scheme: a continual reassessment method (CRM) will be used to guide inclusion of patients in drug dose levels pre-specified based on observations of dose-limiting toxicity. Phase 2 (expansion of cohort): once RP2D will be determined, additional patients will be enrolled, in order to obtain preliminary data about efficacy in a 2 stage Simon's design.
Receives: Drug: Olaparib; Drug: metformin; Drug: metronomic cyclophosphamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin

    Measured: through the 6th week of treatment (cycle 1)

Secondary outcomes (5)

  1. Efficacy of olaparib combined to metronomic cyclophosphamide and metformin

    non-progression rate at 10 weeks, calculated as the combination of stable disease, partial response and complete response defined according to RECIST v.1.1

    Measured: at 10 weeks

  2. Number of patients with adverse events relative to the study treatment olaparib combined to metronomic cyclophosphamide and metformin

    All adverse events relative to the study treatment will be recorded (NCI- Common Terminology for Adverse Events (CTAE) v.4 criteria) during the treatment.

    Measured: through treatment completion (a median of 12 months)

  3. Pharmacodynamic effects of the 3 drugs on circulating tumor DNA (ctDNA),

    The kinetics of circulating tumor DNA (ctDNA), serially measured will be assessed using population kinetic approach and mathematical modeling

    Measured: through treatment completion (a median of 12 months)

  4. Pharmacodynamic effects of the 3 drugs on circulating Insulin Growth Factor (IGF-1)

    The kinetics of Insulin Growth Factor (IGF-1) values serially measured will be assessed using population kinetic approach and mathematical modeling

    Measured: through treatment completion (a median of 12 months)

  5. Pharmacodynamic effects of the 3 drugs on circulating (Cancer Antigen) CA-125 values

    The kinetics of (Cancer Antigen) CA-125 values serially measured will be assessed using population kinetic approach and mathematical modeling

    Measured: through treatment completion (a median of 12 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Apr 2016 (estimated)
  2. Study start23 Sep 2016
  3. Primary completionNov 2018
  4. Study completionJun 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02755844
Sponsor's protocol ID
69HCL15_0321
Other IDs
2015-004364-11, 2015
Acronym
ENDOLA
Status last verified
Sep 2025
First submitted
14 Apr 2016
Last updated
27 May 2026
Results posted
No
Data monitoring committee
Yes

Publications

  • Piffoux M, Leary A, Follana P, Abdeddaim C, Joly F, Bin S, Bonjour M, Boulai A, Callens C, Villeneuve L, Alexandre M, Schwiertz V, Freyer G, Rodrigues M, You B. Olaparib combined to metronomic cyclophosphamide and metformin in women with recurrent advanced/metastatic endometrial cancer: the ENDOLA phase I/II trial. Nat Commun. 2025 Feb 20;16(1):1821. doi: 10.1038/s41467-025-56914-7.

    PubMed 39979249

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Olaparib, metformin and metronomic cyclophosphamide in people with Recurrent Endometrial Cancer, run by Hospices Civils de Lyon at 6 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin (time frame: through the 6th week of treatment (cycle 1)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02755844, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 May 2026.

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