Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer

  • STATUS
    Recruiting
  • End date
    May 26, 2024
  • participants needed
    414
  • sponsor
    Grupo Español de Investigación en Cáncer de Ovario
Updated on 26 January 2021

Summary

Atezolizumab in this study is expected to have a positive benefit-risk profile for the treatment of patients with platinum-sensitive relapse of ovarian cancer. Of interest, atezolizumab is being investigated also in combination with platinum-based doublet chemotherapy in second line (2L)/ third line (3L) platinum-sensitive recurrent ovarian cancer patients in ATALANTE (NCT02891824), which also includes bevacizumab in the combination. The study is proceeding as expected after >100 patients enrolled and under independent Data Monitoring Committee (IDMC) supervision.

Platinum-containing therapy is considered the treatment of choice for patients with platinum-sensitive relapse. However the duration of response and the prolongation of the progression free interval with chemotherapy are usually brief, among other because these chemotherapy regimens cannot be continued until progression as they are associated with neurological, renal and hematological toxicity and cannot generally be tolerated for more than about 6 to 9 cycles.

Niraparib received FDA approval in March 2017 as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Recently, the European Medicines Agency (EMA) has also approved niraparib as maintenance monotherapy. Despite the progress brought about by niraparib, there is a need for a more effective treatment to extend the progression free interval in this patient population. The combination with immune checkpoint inhibitors such as anti-death protein 1 (anti-PD1) or anti-death protein ligand 1 (anti-PD-L1) has a compelling rationale to this aim, especially under the light of the emerging clinical data of this combination.

The use of atezolizumab concurrent to platinum-containing chemotherapy followed by niraparib as maintenance therapy after completion of chemotherapy, as per normal clinical practice, may provide further benefit to patients in terms of prolonging the progression free interval and increasing the interval between lines of chemotherapy, hence delaying further hospitalization and the cumulative toxicities associated with chemotherapy. Additionally, preliminary studies with atezolizumab suggest an acceptable tolerability profile for long term clinical use in recurrent ovarian cancer patients and other indications.

Details
Condition Recurrent Ovarian Carcinoma, Recurrent Ovarian Cancer
Treatment carboplatin, Placebo, Gemcitabine, Paclitaxel, Pegylated Liposomal Doxorubicin (PLD), Atezolizumab, Niraparib
Clinical Study IdentifierNCT03598270
SponsorGrupo Español de Investigación en Cáncer de Ovario
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Are you female?
Do you have Recurrent Ovarian Carcinoma?
Do you have any of these conditions: Recurrent Ovarian Carcinoma or Recurrent Ovarian Cancer?
Do you have any of these conditions: Recurrent Ovarian Cancer or Recurrent Ovarian Carcinoma?
Patients 18 years old
Life expectancy 3 months
Signed informed consent and ability to comply with treatment and follow-up
Histologically confirmed diagnosis (cytology alone excluded) of high- grade serous or endometrioid ovarian, primary peritoneal or tubal carcinoma
Breast Cancer (BRCA) mutational status is known (germline or somatic)
Relapsed disease more than 6 months after the last platinum dose
No more than 2 prior lines of chemotherapy are allowed, and the last one must contain a platinum-based regimen
At least one measurable lesion to assess response by RECIST v1.1 criteria
Mandatory de novo tumor biopsy (collected within 3 months prior to randomization) sent to HistoGene X as a formalin-fixed, paraffin-embedded (FFPE) sample for PD-L1 status determination for randomization
Two additional tumour samples are needed: Archival tumor sample must be available for exploratory PD-L1 testing in archival tissue and archival or "de novo" tissue sample for biomarkers must also be available
Performance status determined by Eastern Cooperative Oncology Group (ECOG) score of 0-1
Normal organ and bone marrow function
Haemoglobin 10.0 g/dL
Absolute neutrophil count (ANC) 1.5 x 109/L
Lymphocyte count 0.5 109/L
Platelet count 100 x 109/L
Total bilirubin 1.5 x institutional upper limit of normal (ULN)
Serum albumin 2.5 g/dL
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) 2.5 x ULN, unless liver metastases are present in which case they must be 5 x ULN
Serum creatinine 1.5 x institutional ULN or calculated creatinine clearance 30 mL/min using the Cockcroft-Gault equation
Patients not receiving anticoagulant medication must have an International Normalized Ratio (INR) 1.5 and an Activated ProThrombin Time (aPTT) 1.5 x ULN
Negative Test Results for Hepatitis
Toxicities related to previous treatments must be recovered to < grade 2
Female participants must be postmenopausal or surgically sterile or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods
Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment
Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment

Exclusion Criteria

Non-epithelial tumor of the ovary, the fallopian tube or the peritoneum
Ovarian tumors of low malignant potential or low grade
Other malignancy within the last 5 years except curatively treated non-melanoma skin cancer, in situ cancer of the cervix and ductal carcinoma in situ (DCIS)
Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered (Grade 2) from the effects of any major surgery at randomization
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1
Administration of other chemotherapy drugs, anticancer therapy or anti-neoplastic hormonal therapy, or treatment with other investigational agents or devices within 28 days prior to randomization, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, or anticipation to do it during the trial treatment period (non-investigational hormonal replacement therapy is permitted)
Palliative radiotherapy (e.g., for pain or bleeding) within 6 weeks prior to randomization or patients who have not completely recovered (Grade 2) from the effects of previous radiotherapy
Current or recent (within 10 days prior to randomization) chronic use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day)
Clinically significant (e.g. active) cardiovascular disease
Resting ECG with corrected QT interval (QTc) >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression
Left ventricular ejection fraction defined by multigated acquisition/echocardiogram (MUGA/ECHO) below the institutional lower limit of normal
History or evidence upon neurological examination of central nervous system (CNS) disorders (e.g. uncontrolled epileptic seizures) unless adequately treated with standard medical therapy
Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease
Uncontrolled tumor-related pain
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed
Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
Pregnant or lactating women
Simultaneously receiving therapy in any interventional clinical trial
Prior treatment with CD137 agonists or immune checkpoint stimulating or blockade therapies, such as anti-PD1, anti-PDL1 or anti-CTLA4 therapeutic antibodies
Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener's granulomatosis, Sjgren's syndrome, Guillain-Barr syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis
Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)
Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
Active tuberculosis
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Administration of a live, attenuated vaccine (including against influenza) within 4 weeks prior to Cycle 1, Day 1 or anticipation that it will be administered at any time during the treatment period of the study or within 5 months after the final dose of atezolizumab
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation or allergy to any of the other drugs included in the protocol or their solvents (including to Cremophor)
Patient has had any known Grade 3 hematological toxicity anemia, neutropenia or thrombocytopenia due to prior cancer chemotherapy that persisted >4 weeks and was related to the most recent treatment
Patient has received prior treatment with a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor in the recurrent setting or has participated in a study where any treatment arm included administration of a PARP inhibitor in the recurrent setting, unless the patient is unblinded and there is evidence of not having received a PARP inhibitor. Patients that received PARP inhibitor as front line are eligible for the study. The duration of exposure to PARPi following front line therapy needs to be 18 months for BRCA mutated patients and 12 months for BRCA wild type patients
Patient has any known history or current diagnosis of Myelodysplasic syndrome (MDS) or Anaplastic Myeloid Leukemia (AML)
Previous allogeneic bone marrow transplant or previous solid organ transplantation
Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment
Participant has any known hypersensitivity to niraparib components or excipients
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