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

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ClinicalTrials.gov Identifier: NCT02755844
Recruitment Status : Not yet recruiting
First Posted : April 29, 2016
Last Update Posted : April 29, 2016
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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.


Condition or disease Intervention/treatment Phase
Recurrent Endometrial Cancer Drug: Olaparib Drug: metformin Drug: metronomic cyclophosphamide Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : April 2016
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Olaparib, metformin and metronomic cyclophosphamide

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.

Drug: Olaparib

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.


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

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




Primary Outcome Measures :
  1. Recommended phase 2 trial (RP2D) dose of olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: through the 6th week of treatment (cycle 1) ]

Secondary Outcome Measures :
  1. Efficacy of olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: at 10 weeks ]
    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

  2. Number of patients with adverse events relative to the study treatment olaparib combined to metronomic cyclophosphamide and metformin [ Time Frame: through treatment completion (a median of 12 months) ]
    All adverse events relative to the study treatment will be recorded (NCI- Common Terminology for Adverse Events (CTAE) v.4 criteria) during the treatment.

  3. Pharmacodynamic effects of the 3 drugs on circulating tumor DNA (ctDNA), [ Time Frame: through treatment completion (a median of 12 months) ]
    The kinetics of circulating tumor DNA (ctDNA), serially measured will be assessed using population kinetic approach and mathematical modeling

  4. Pharmacodynamic effects of the 3 drugs on circulating Insulin Growth Factor (IGF-1) [ Time Frame: through treatment completion (a median of 12 months) ]
    The kinetics of Insulin Growth Factor (IGF-1) values serially measured will be assessed using population kinetic approach and mathematical modeling

  5. Pharmacodynamic effects of the 3 drugs on circulating (Cancer Antigen) CA-125 values [ Time Frame: through treatment completion (a median of 12 months) ]
    The kinetics of (Cancer Antigen) CA-125 values serially measured will be assessed using population kinetic approach and mathematical modeling



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Ages Eligible for Study:   18 Years to 81 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 ≤ 2
  • 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 granulocyte 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, according to the Modification of the Diet in Renal Disease (MDRD) formula >= 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 a medically acceptable method of birth control 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, according to the MDRD formula); 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.
  • 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.

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): NCT02755844


Contacts
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Contact: Benoit YOU, Doctor 4 788 643 18 ext +33 benoit.you@chu-lyon.fr
Contact: Marine DUPUIS 4 788 612 25 ext +33 marine.dupuis01@chu-lyon.fr

Locations
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France
Centre Hospitalier Lyon Sud Not yet recruiting
Pierre Benite, France, 69495
Contact: Benoit YOU         
Contact: Marine DUPUIS         
Principal Investigator: Benoit YOU, MD         
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
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Principal Investigator: Benoit YOU, Doctor Hospices Civils de Lyon

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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT02755844     History of Changes
Other Study ID Numbers: 69HCL15_0321
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: April 29, 2016
Last Verified: April 2016

Keywords provided by Hospices Civils de Lyon:
endometrial carcinomas
metronomic cyclophosphamide
metformin
olaparib
dose-escalation study

Additional relevant MeSH terms:
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Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Metformin
Uterine Diseases
Genital Diseases, Female
Cyclophosphamide
Olaparib
Hypoglycemic Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors