The EPOCH Study: Phase II Open Labelled Study Investigating the Use of Single Agent Eribulin and Eribulin in Combination With Pembrolizumab in Relapsed Tubo-ovarian or Uterine Carcinosarcoma
Overview
- Phase
- Phase 2
- Intervention
- Eribulin Mesylate
- Conditions
- Ovarian Carcinosarcoma
- Sponsor
- Australia New Zealand Gynaecological Oncology Group
- Enrollment
- 30
- Locations
- 6
- Primary Endpoint
- Clinical Benefit Rate (CBR) by RECIST v1.1 in combination therapy arm
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
The EPOCH study population is patients with tubo-ovarian carcinosarcoma or uterine carcinosarcoma with evidence of recurrence or progression.
The study aims to determine the activity of eribulin as a single agent and the combination of eribulin and pembrolizumab as measured by clinical benefit rate (CBR) at 12 weeks.
Additionally, the study aims to establish whether high mobility group A2 (HMGA2) protein expression is a good functional biomarker to predict response to eribulin and pembrolizumab.
Detailed Description
EPOCH (Eribulin and Pembrolizumab in Tubo-Ovarian and Uterine Carcinosarcoma) is an international clinical trial, which aims to improve outcomes in people with the rare and highly lethal Ovarian Carcinosarcoma (OCS) or Uterine Carcinosarcoma (UCS) malignancies. The underlying study rationale is based on robust preclinical evidence that demonstrated that eribulin, a microtubule inhibitor, can reprogram the tumour microenvironment, reversing epithelial mesenchymal transition (EMT) in these mesenchymal cancers, and potentiate the response to immune checkpoint blockade. In addition, expression of HMGA2, a high mobility group protein has been associated with activation of EMT process and may be a predictive biomarker of eribulin-responsive cancers. This study is aimed at translating these laboratory findings to the clinic and treat patients with recurrent OCS and UCS with eribulin and the immune checkpoint inhibitor pembrolizumab, which targets and blocks the programmed cell death receptor 1 (PD-1).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of written informed consent prior to any study specific procedures and the ability to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations.
- •Patients \> 18 years old who have a histologically confirmed tubo-ovarian carcinosarcoma or uterine carcinosarcoma with evidence of recurrence or progression. The component of sarcoma in the diagnostic pathology sample must be equal to or \> 5% of tumour.
- •Must have Positron Emission Tomography (PET), Computerized Tomography CT, or Magnetic Resonance Imaging (MRI) -proven relapsed disease after completion of at least one line and not more than two lines of chemotherapy.
- •Must have at least one evaluable measurable lesion (other than the lesion that will be used for biopsy) using standard techniques according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1) guidelines (Appendix 1).
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 5). Evaluation of ECOG is to be performed within 28 days prior to the first dose of the study intervention.
- •Have adequate organ function as defined below (refer also Appendix 6).
- •Absolute neutrophil count (ANC) ≥1.5 x 109/L
- •Platelets ≥100 x 109/L
- •Haemoglobin (Hb) ≥90 g/L or ≥5.6 mmol/L (criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks).
- •Creatinine ≤ 1.5 x Upper Limit Normal (ULN); OR Creatinine Clearance (CrCl) ≥ 30 mL/min (calculated per institutional standard) for participants with creatinine levels \>1.5 ULN (glomerular filtration rate, GFR, can also be used in place of creatinine or CrCl). (Patients with moderate renal impairment (CrCl 30-49ml/min) will receive a 25% reduced dose of eribulin).
Exclusion Criteria
- •Prior line of treatment involving immunotherapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor. This criteria is applicable for both intervention arms as patients may cross-over from the non-immunotherapy arm during their study participation.
- •Prior treatment with eribulin for any malignancy.
- •Absence of a second disease site suitable for biopsy
- •Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the first dose of the study intervention.
- •Has active autoimmune disease (such as Systemic Lupus Erythematosus) that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- •A POCBP who has a positive urine pregnancy test within 7 days prior to the first dose of the study intervention (see Appendix 7). If the urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Has received prior radiotherapy within 2 weeks of the start of the study intervention. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease.
- •Known central nervous system malignancy or metastasis, including leptomeningeal metastasis or carcinomatous meningitis, unless adequately treated and patients are neurologically stable for at least one month prior to enrolment. Patients must be either off corticosteroids or on stable or decreasing dose of \< /=10 mg daily prednisone (or equivalent) within 28 days prior to the first dose of the study intervention. In the case of short-term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg daily of prednisone or an equivalent corticosteroid, the required washout period prior to starting the first dose of the study intervention is 7 days. Anticonvulsants are allowed to be continued except for those which interfere with the study interventions or are associated with liver toxicity. However, patients receiving anticonvulsants must be discussed with Study Chair or Acting Chair of Trial Management Committee (TMC) prior to their enrolment to the study.
- •Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease or ulcerative colitis).
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study intervention.
Arms & Interventions
Arm 1 - Single agent eribulin arm
Eribulin until progression of disease (PD) as defined by RECIST v1.1, unacceptable toxicity or physician/patient discretion or choice to cease treatment. Patients who progress on the single agent eribulin arm may receive combination eribulin and pembrolizumab.
Intervention: Eribulin Mesylate
Arm 2 - Combination eribulin and pembrolizumab arm
Eribulin for a maximum of 6 cycles. Pembrolizumab until PD or a maximum of 35 cycles (including the 6 cycles where it is administered in combination with eribulin) or until unacceptable toxicity or physician/patient discretion or choice to cease treatment.
Intervention: Eribulin Mesylate
Arm 2 - Combination eribulin and pembrolizumab arm
Eribulin for a maximum of 6 cycles. Pembrolizumab until PD or a maximum of 35 cycles (including the 6 cycles where it is administered in combination with eribulin) or until unacceptable toxicity or physician/patient discretion or choice to cease treatment.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Clinical Benefit Rate (CBR) by RECIST v1.1 in combination therapy arm
Time Frame: 12 Weeks
CBR defined as Partial Response (PR), Complete Response (CR) or Stable Disease (SD) by RECIST v1.1 in the combination therapy arm.
Secondary Outcomes
- Health related Quality of Life using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for cancer patients (QLQ C30)(Up to 4 years)
- Health related Quality of Life using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire module for Ovarian Cancer patients (OV28)(Up to 4 years)
- Clinical Benefit Rate (CBR) by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 in single agent therapy arm(12 weeks)
- Objective Response Rate (ORR) in both the single agent eribulin and combination eribulin/pembrolizumab arms(12 weeks)
- Overall Survival (OS)(Up to 4 years)
- Adverse events(Up to 4 years)
- Clinical Benefit Rate (CBR) by iRECIST (modified RECIST guidelines for use in cancer immunotherapy trials)(12 weeks)
- Time to progression in the combination therapy arm(Up to 3 years)
- Progression free survival (PFS)(Up to 4 years)