Clinical Trials /

Olaparib and Durvalumab With Carboplatin, Etoposide, and/or Radiation Therapy for the Treatment of Extensive-Stage Small Cell Lung Cancer, PRIO Trial

NCT04728230

Description:

This phase I/II trials investigates the side effects of olaparib and durvalumab and how well it works in combination with carboplatin, etoposide, and/or radiation therapy in treating patients with extensive stage-small cell lung cancer (ES-SCLC) who have not received treatment for their disease. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy sources to kill tumor cells and shrink tumors. Giving olaparib and durvalumab together with carboplatin, etoposide, and/or radiation therapy may help treat patients with ES-SCLC.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib and Durvalumab With Carboplatin, Etoposide, and/or Radiation Therapy for the Treatment of Extensive-Stage Small Cell Lung Cancer, PRIO Trial
  • Official Title: A Phase I/II Trial of PARP Inhibition, Radiation, and Immunotherapy in Patients With Extensive-Stage Small Cell Lung Cancer (ES-SCLC) - PRIO Trial

Clinical Trial IDs

  • ORG STUDY ID: 2020-0612
  • SECONDARY ID: NCI-2020-06178
  • SECONDARY ID: 2020-0612
  • NCT ID: NCT04728230

Conditions

  • Extensive Stage Lung Small Cell Carcinoma
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (chemo-immunotherapy, radiation therapy)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (chemo-immunotherapy, radiation therapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment (chemo-immunotherapy, radiation therapy)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (chemo-immunotherapy, radiation therapy)

Purpose

This phase I/II trials investigates the side effects of olaparib and durvalumab and how well it works in combination with carboplatin, etoposide, and/or radiation therapy in treating patients with extensive stage-small cell lung cancer (ES-SCLC) who have not received treatment for their disease. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy sources to kill tumor cells and shrink tumors. Giving olaparib and durvalumab together with carboplatin, etoposide, and/or radiation therapy may help treat patients with ES-SCLC.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the toxicity and feasibility of sequential treatment with olaparib, thoracic
      radiotherapy (TRT)/durvalumab, and olaparib/durvalumab for consolidation and maintenance
      therapy in patients status post (s/p) chemoimmunotherapy for ES-SCLC.

      SECONDARY OBJECTIVE:

      I. To assess the efficacy of sequential treatment with olaparib, TRT/durvalumab, and
      olaparib/durvalumab for consolidation and maintenance therapy in patients s/p
      chemoimmunotherapy for ES-SCLC.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemo-immunotherapy, radiation therapy)ExperimentalSee detailed description.
  • Carboplatin
  • Durvalumab
  • Etoposide
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of signed and dated written informed consent form prior to any mandatory
             study specific procedures, sampling, and analyses. For inclusion in i) the optional
             exploratory genetic research and ii) the optional biomarker research, patients must
             fulfill the following criteria:

               -  Provision of informed consent for genetic research prior to collection of sample;

               -  Provision of informed consent for biomarker research prior to collection of
                  sample;

               -  If a patient declines to participate in the optional exploratory genetic research
                  or the optional biomarker research, there will be no penalty or loss of benefit
                  to the patient. The patient will not be excluded from other aspects of the study

          -  At least one lesion (measurable and/or non-measurable) that can be accurately assessed
             at baseline by computed tomography (CT) and is suitable for repeated assessment

          -  Patients with previously treated brain metastases that are asymptomatic for at least
             14 days and only require prednisone equivalent of 10 mg daily or less prior to study
             treatment

          -  Histological or cytological documented ES-SCLC: American Joint Committee on Cancer
             (AJCC) stage IV SCLC (T any, N any, M1 a/b), including patients with T3-4 due to
             multiple lung nodules that are too extensive or have tumor/nodal volume that is too
             large to be encompassed in a tolerable radiation plan

          -  No prior systemic therapy for ES-SCLC, including, but not limited to, chemotherapy,
             PARP inhibitor, and PD-1/PD-L1 checkpoint inhibitors. Palliative radiation is allowed
             if completed a minimum of three days prior to beginning of study treatment

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at enrollment

          -  Body weight > 30 kg

          -  Hemoglobin >=10.0 g/dL with no blood transfusion in the past 28 days (measured within
             28 days prior to administration of study treatment)

          -  Absolute neutrophil count >= 1.5 x 10^9 /L (measured within 28 days prior to
             administration of study treatment)

          -  Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of
             study treatment)

          -  Serum bilirubin =<1.5 x institutional upper limit of normal (ULN) (measured within 28
             days prior to administration of study treatment)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
             institutional ULN, unless liver metastases are present in which case they must be =< 5
             x ULN (measured within 28 days prior to administration of study treatment)

          -  Calculated estimated creatinine clearance >= 51 mL/min using the Cockcroft- Gault
             equation or based on a 24-hour urine test (measured within 28 days prior to
             administration of study treatment)

          -  Evidence of post-menopausal status or evidence of non-childbearing status for women of
             childbearing potential: negative urine or serum pregnancy test within 28 days of study
             treatment and confirmed prior to treatment on day 1. Postmenopausal status is defined
             as:

               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
                  post-menopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses > 1 year ago

               -  Chemotherapy-induced menopause with > 1-year interval since last menses

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

               -  Women of childbearing potential and their partners, who are sexually active, must
                  agree to the use of TWO highly effective forms of contraception in combination.
                  This should be started from the signing of the informed consent and continue
                  throughout the period of taking study treatment and for at least 3 months after
                  last dose of study drug(s)

               -  Male patients must use a condom during treatment and for 3 months after the last
                  dose of study treatment when having sexual intercourse with a pregnant woman or
                  with a woman of childbearing potential. Female partners of male patients should
                  also use a highly effective form of contraception if they are of childbearing
                  potential. Male patients should not donate sperm throughout the period of taking
                  study treatment and for 3 months following the last dose of study treatment

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including
             follow-up

        Exclusion Criteria:

          -  Histology other than SCLC

          -  Prior systemic therapy for ES-SCLC (e.g. chemotherapy, PARP inhibitor, other DNA
             damage response [DDR] inhibitors, PD-1/PD-L1 inhibitors)

          -  Patients with untreated brain metastases

          -  Patients with spinal cord compression unless considered to have received definitive
             treatment for this and evidence of clinically stable disease for 28 days

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of study treatment and patients must have recovered from any effects of any
             major surgery. Note: Local surgery of isolated lesions for palliative intent is
             acceptable

          -  Other malignancy unless curatively treated with no evidence of disease for >= 3 years
             except:

               -  Adequately treated non-melanoma skin cancer.

               -  Curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS);
                  stage 1, grade 1 endometrial carcinoma; and in situ bladder cancer

          -  Any concurrent anticancer therapy

          -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
             cardiac conditions, as judged by the investigator (e.g. unstable ischemia,
             uncontrolled symptomatic arrhythmia, congestive heart failure, QT corrected by
             Fridericia (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or patients
             with congenital long QT syndrome

          -  Current or prior use of immunosuppressive medication within 14 days prior to cycle 1
             (C1) of study treatment, with the exceptions of intranasal and inhaled
             corticosteroids, or systemic corticosteroids at physiological doses, which are not to
             exceed 10 mg/day of prednisone or an equivalent corticosteroid

          -  Active or prior documented autoimmune disease within the past 2 years. NOTE: vitiligo,
             alopecia, chronic skin condition that does not require systemic therapy, psoriasis not
             requiring systemic treatment (within the past 2 years), and hypothyroidism (if stable
             on hormonal therapy) are not exclusion criteria

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis) or pneumonitis

          -  Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV)

          -  Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

          -  Patients considered high medical risk due to a serious, uncontrolled medical disorder,
             non-malignant systemic disease or active, uncontrolled infection. Examples include,
             but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months)
             myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord
             compression, superior vena cava syndrome, extensive interstitial bilateral lung
             disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder
             that prohibits obtaining informed consent

          -  Patients with myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) or with
             features suggestive of MDS/AML

          -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable outside of 28 days prior to
             treatment)

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting study treatment is 2 weeks

          -  Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
             moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
             period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital
             and 3 weeks for other agents

          -  Participation in another clinical study with an investigational product (IP)
             administered in the last 6 months

          -  Involvement in the planning and/or conduct of the study

          -  Previous enrollment in the present study

          -  Receipt of live attenuated vaccination within 30 days prior to study entry

          -  Female subjects who are pregnant, breast-feeding or male or female patients of
             reproductive potential who are not employing two highly effective methods of birth
             control

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Known allergy or hypersensitivity to durvalumab, olaparib or any excipients

          -  Any persistent toxicity National Cancer Institute (NCI) Common Terminology Criteria
             for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 from previous anticancer therapy
             with the exception of alopecia, vitiligo, and the laboratory values defined in the
             inclusion criteria.

               -  Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the study physician

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  study treatment may be included only after consultation with the study physician
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicity
Time Frame:From start of olaparib, until end of cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Toxicity data by type and severity will be summarized in frequency tables.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Time from starting chemo-immunotherapy until disease progression or death from any cause, assessed up to 1 year
Safety Issue:
Description:Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. PFS will be compared to the pre-specified parameter obtained from historical data of comparable patients with extensive-stage small cell lung cancer (ES-SCLC) treated with frontline etoposide plus either cisplatin or carboplatin (EP) chemotherapy followed by thoracic radiation. Will be estimated using the Kaplan-Meier method. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox regression model will be applied to evaluate the effect of potential covariates on PFS.
Measure:Overall survival (OS)
Time Frame:Time from starting chemo-immunotherapy until death from any cause, assessed up to 1 year
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Cox regression model will be applied to evaluate the effect of potential covariates on OS.
Measure:Overall response rate (ORR)
Time Frame:Up to 1 year
Safety Issue:
Description:The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions.
Measure:Intra- and extra-thoracic recurrence rates
Time Frame:Up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

January 28, 2021