Brief Title
Safety and Efficacy of Metronomic Cyclophosphamide, Metformin and Olaparib in Endometrial Cancer Patients
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
Brief 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. 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.
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.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin
Secondary Outcome
Efficacy of olaparib combined to metronomic cyclophosphamide and metformin
Condition
Recurrent Endometrial Cancer
Intervention
Olaparib
Study Arms / Comparison Groups
Olaparib, metformin and metronomic cyclophosphamide
Description: Phase 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
35
Start Date
September 23, 2016
Completion Date
June 2020
Primary Completion Date
November 2018
Eligibility Criteria
Inclusion Criteria:
- 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
- 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
Exclusion Criteria:
- 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.
- 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.
Gender
Female
Ages
18 Years - 81 Years
Accepts Healthy Volunteers
No
Contacts
Benoit YOU, Doctor, ,
Location Countries
France
Location Countries
France
Administrative Informations
NCT ID
NCT02755844
Organization ID
69HCL15_0321
Responsible Party
Sponsor
Study Sponsor
Hospices Civils de Lyon
Study Sponsor
Benoit YOU, Doctor, Principal Investigator, Hospices Civils de Lyon
Verification Date
December 2019