Clinical Trials /

Sirolimus and Durvalumab for the Treatment of Stage I-IIIA Non-small Cell Lung Cancer

NCT04348292

Description:

This trial studies the side effects of sirolimus and durvalumab and to see how well they work in treating patients with stage I-IIIA non-small cell lung cancer. Sirolimus is an oral medication that blocks the mTOR cellular pathway which may help the immune system work better. 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. Giving sirolimus before durvalumab may help the immune system get rid of cancer.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sirolimus and Durvalumab for the Treatment of Stage I-IIIA Non-small Cell Lung Cancer
  • Official Title: A Phase 1b Neoadjuvant Trial of Sirolimus Followed by Durvalumab (MEDI4736) in Resectable Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00116422
  • SECONDARY ID: NCI-2019-07427
  • SECONDARY ID: Winship4867-19
  • SECONDARY ID: P30CA138292
  • SECONDARY ID: P50CA217691
  • NCT ID: NCT04348292

Conditions

  • Lung Non-Small Cell Carcinoma
  • Stage I Lung Cancer AJCC v8
  • Stage IA1 Lung Cancer AJCC v8
  • Stage IA2 Lung Cancer AJCC v8
  • Stage IA3 Lung Cancer AJCC v8
  • Stage IB Lung Cancer AJCC v8
  • Stage II Lung Cancer AJCC v8
  • Stage IIA Lung Cancer AJCC v8
  • Stage IIB Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Treatment (sirolimus, durvalumab)
SirolimusAY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217Treatment (sirolimus, durvalumab)

Purpose

This trial studies the side effects of sirolimus and durvalumab and to see how well they work in treating patients with stage I-IIIA non-small cell lung cancer. Sirolimus is an oral medication that blocks the mTOR cellular pathway which may help the immune system work better. 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. Giving sirolimus before durvalumab may help the immune system get rid of cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of sirolimus followed by durvalumab as neoadjuvant
      treatment II. To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant
      treatment for stage I, II, and IIIA non-small cell lung cancer (NSCLC)

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of sirolimus in combination with durvalumab as neoadjuvant
      treatment for stage I, II, and IIIA NSCLC II. To evaluate response to sirolimus in
      combination with durvalumab in patients with PD-L1-positive versus (vs.) PD-L1-negative
      tumors III. To evaluate the association between blood mutation burden and response to
      sirolimus and durvalumab

      EXPLORATORY OBJECTIVES:

      I. To evaluate the immune-mediated effects of combination sirolimus and durvalumab II. To
      investigate tumor and immune microenvironment changes in tissue samples

      OUTLINE:

      Patients receive sirolimus orally (PO) once daily (QD) on days 1-21 in the absence of disease
      progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab
      intravenously (IV) over 1 hour. Treatment with durvalumab repeats every 21 days for up to 2
      cycles in the absence of disease progression or unacceptable toxicity. Within a 2-3 week
      period after the second dose of durvalumab, but not earlier than two weeks after the
      administration of durvalumab, patients undergo standard of care surgery.

      After completion of study treatment, patients are followed up every 3 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sirolimus, durvalumab)ExperimentalPatients receive sirolimus PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab IV over 1 hour. Treatment with durvalumab repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within a 2-3 week period after the second dose of durvalumab, but not earlier than two weeks after the administration of durvalumab, patients undergo standard of care surgery.
  • Durvalumab
  • Sirolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with pathologically documented NSCLC: Stage I, II, IIIa NSCLC based on 8th
             edition of American Joint Committee on Cancer (AJCC) Non-small cell Lung Cancer
             Staging system

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol. Written informed consent and any locally required authorization (eg, Health
             Insurance Portability and Accountability Act in the United States [US]) obtained from
             the patient/legal representative prior to performing any protocol-related procedures,
             including screening evaluations

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

          -  Life expectancy of >= 26 weeks

          -  Body weight > 30 kg

          -  Hemoglobin >= 9.0 g/dL

          -  Absolute neutrophil count (ANC) 1.5 x 10^9/L (>= 1500 per mm^3)

          -  Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal unless liver metastases are present, in
             which case it must be =< 5 x ULN

          -  Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine CL > 40 mL/min
             by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
             collection for determination of creatinine clearance

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women < 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women >= 50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses > 1 year ago, had
                  chemotherapy-induced menopause with last menses > 1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy)

          -  Patient 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

          -  Patients must consent to pre-treatment research biopsy and study peripheral blood
             collection

          -  Patients must have measurable disease, defined by RECIST v 1.1

          -  Patient is able to take oral medications

          -  Patient consents to heavy water (D2O) self-administration if on optional heavy water
             labelling study

        Exclusion Criteria:

          -  Patients who have had prior therapy for lung cancer including chemotherapy, hormonal
             therapy, or radiotherapy

          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study

          -  Prior treatment with anti-PD-1, anti-PDL-1, other PD-1/PDL-1 pathway targeting agents,
             or mTOR inhibition

          -  History of allogenic organ transplantation

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Patients without active disease in the last 5 years may be included but only
                  after consultation with the study physician

               -  Patients with celiac disease controlled by diet alone

          -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring adverse events (AEs) or compromise the ability of the patient to
             give written informed consent

          -  History of another primary malignancy except for

               -  Malignancy treated with curative intent and with no known active disease >= 5
                  years before the first dose of investigational product (IP) and of low potential
                  risk for recurrence

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease

          -  QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms.
             Patient safety and the cardiac SKG should be consulted as needed

          -  History of active primary immunodeficiency

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis [TB] testing
             in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
             surface antigen [HBsAg] result), hepatitis C. Patients with a past or resolved HBV
             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
             of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are
             eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (e.g., computed
                  tomography [CT] scan premedication)

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy

          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients

          -  Prior randomization or treatment in a previous durvalumab clinical study regardless of
             treatment arm assignment

          -  Patients with a history of idiopathic pulmonary fibrosis, pneumonitis (including drug
             induced), organizing pneumonia, or evidence of active pneumonitis on screening chest
             computed tomography (CT) scan

          -  Inability to stop prohibited concomitant medications

          -  Judgment by the investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions and
             requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame:2 years
Safety Issue:
Description:Other adverse events will be listed and summarized by severity, seriousness, and by system organ class. The number and percentage of subjects who experience AEs will be presented in tabular and/or graphical format and summarized descriptively, where appropriate. The frequency of overall toxicity, categorized by toxicity grades 1 through 5, will be described.

Secondary Outcome Measures

Measure:Complete pathologic response rates for PDL-1 negative and PDL-1 positive patients
Time Frame:2 years
Safety Issue:
Description:A comparison of both the complete pathologic response and investigator assessed response rates per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 rates between the PD-L1 positive and PD-L1 negative groups will be performed by calculating the lower bound of a one-sided 80% CI for the difference, complete pathologic response for PDL-1 positive patients − complete pathologic response for PDL-1 negative patients. Chi-square test or Fisher's exact test will be used to compare the efficacy in term of response rate between the different groups stratified by other factors, respectively. Logistics regression model will be further employed to test the adjusted effect of each other factor on the response rate after adjusting for other clinical factors and demographic factors, respectively. Correlation of response will be performed for tumor mutation burden using spearman correlation coefficient and tested with Wald's test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

Last Updated

April 13, 2020