Clinical Trials /

Proton Based Cardiac Sparing Accelerated Fractionated RadioTherapy in Unresectable NSCLC

NCT03818776

Description:

The purpose of this study is to treat participants with the combination of durvalumab (the study drug) and proton beam therapy. Proton beam therapy is a type of radiotherapy (RT) with a unique characteristic where the proton stops at a specific depth according to its energy. This may be advantageous in treating lung cancer because it allows for a sufficient tumor dose that may improve local control and survival while sparing normal organs at risk, such as the heart, lung, and spinal cord.

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

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Proton Based Cardiac Sparing Accelerated Fractionated RadioTherapy in Unresectable NSCLC
  • Official Title: A Pilot Trial of Proton Based Cardiac Sparing Accelerated Fractionated RadioTherapy in Unresectable Non-Small Cell Lung Cancer With Extended Durvalumab Therapy (PARTICLE-D)

Clinical Trial IDs

  • ORG STUDY ID: CASE1518
  • NCT ID: NCT03818776

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Arm 1 - 60 CGyE in 20 fractions

Purpose

The purpose of this study is to treat participants with the combination of durvalumab (the study drug) and proton beam therapy. Proton beam therapy is a type of radiotherapy (RT) with a unique characteristic where the proton stops at a specific depth according to its energy. This may be advantageous in treating lung cancer because it allows for a sufficient tumor dose that may improve local control and survival while sparing normal organs at risk, such as the heart, lung, and spinal cord.

Detailed Description

      All study participants will receive the same study intervention, which will consist of proton
      based external beam radiation therapy with concurrent Durvalumab starting one week before RT.
      Radiation will be delivered using cardiac sparing accelerated fractionated proton radiation.
      Radiation will have two dose escalation schemes followed by an expansion cohort for a total
      of approximately 24 participants enrolled at University Hospitals Cleveland Medical Center.

      The objectives of this study are to evaluate the safety and feasibility of combination of
      durvalumab with two different schemes for accelerated fractionation proton radiation in
      participants who are unable to tolerate concurrent chemoradiation therapy. This will also
      include the evaluation of adverse events resulting from these treatment schemes.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1 - 60 CGyE in 20 fractionsExperimentalProton based external beam radiation therapy with concurrent Durvalumab starting one week before RT. Radiation will follow dose escalation scheme: 60 CGyE in 20 fractions (3+3 participants, 3-6 total)
  • Durvalumab
Arm 2 - 69 CGyE in 23 fractions followed by expansion cohort aExperimentalProton based external beam radiation therapy with concurrent Durvalumab starting one week before RT. Radiation will follow dose escalation scheme: 69 CGyE in 23 fractions (3+3 participants, 3-6 total) Followed by expansion cohort at identified RP2 dose (12 participants)
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          -  ECOG performance status 0-2

          -  Body Weight >30kg

          -  Must have anticipated life expectancy of at least 12 weeks

          -  Must be histologically or cytologically confirmed to be non-small cell lung cancer
             (NSCLC) confirmed by biopsy within 90 days of registration.

          -  Any tumor PD-L1 expression is allowed (including 0% to 100%, or unknown at time of
             study enrollment)

          -  AJCC 8th Stage IIA-IIIC.

          -  Must be deemed by Specialist or tumor board decision to not be a candidate for
             surgical resection or the participant refuses resection. Being deemed unresectable can
             be for any reason, including but not limited to: tumor location, tumor
             characteristics, operative risks, poor participant lung function, participant age or
             medical comorbidity.

          -  Must be deemed by Medical Oncologist or tumor board decision to not be a candidate for
             or able to tolerate standard cisplatinum based doublet concurrent chemoradiation
             therapy or the participant refuses chemotherapy. Being deemed not a chemotherapy
             candidate can be for any reason, including but not limited to: age, medical
             comorbidity, end organ dysfunction.

          -  Pulmonary function testing performed within 365 days prior to registration. .
             Sufficient lung function as judged by the primary investigator based on anticipated
             radiation fields, with a minimum of FEV1 ≥ 0.7 Liter or ≥ 30% and DLCO ≥ 30% with or
             without bronchodilator within 365 days prior to registration.

          -  Adequate normal organ and marrow function as defined below:

          -  Haemoglobin ≥9.0 g/dL

          -  Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)

          -  Platelet count ≥75 x 109/L (>75,000 per mm3)

          -  Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply
             to participants with confirmed Gilbert's syndrome (persistent or recurrent
             hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
             hepatic pathology), who will be allowed only in consultation with their physician.

          -  AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal

          -  Measured creatinine clearance (CL) >30 mL/min or Calculated creatinine CL>30 mL/min by
             the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection
             for determination of creatinine clearance:

          -  Males:

        Creatinine CL (mL/min) = (Weight (kg) x (140 - Age)) / (72 x serum creatinine (mg/dL))

          -  Females:

        Creatinine CL (mL/min) = (Weight (kg) x (140 - Age)) / (72 x serum creatinine (mg/dL)) x
        0.85

          -  Subjects must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal participants. 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).

          -  Participant 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:

          -  Prior large field thoracic radiation therapy is not allowed except for at the
             discretion of the primary investigator. Prior SBRT to contralateral lung, or breast
             radiation greater than 3 years prior is allowed. Other prior thoracic radiation is
             allowed at the discretion of the primary investigator.

          -  Prior radiation therapy, or immunotherapy for current diagnosis of NSCLC

          -  Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

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

          -  History of another primary malignancy except for:

          -  Malignancy treated with curative intent and with no known active disease ≥2 years
             before the first dose of 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 (i.e. breast) without evidence of disease

          -  Low risk prostate cancer which has been treated or is undergoing active surveillance.

          -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

          -  Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
             consultation with the Study Physician.

          -  Participants with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with durvalumab may be included only after consultation with the Study
             Physician.

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP.

          -  Judgment by the investigator that the participant is unsuitable to participate in the
             study and the participant is unlikely to comply with study procedures, restrictions
             and requirements

        Medication Specific Exclusion Criterion:

          -  History of primary immunodeficiency

          -  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:

          -  Participants with vitiligo or alopecia

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

          -  Any chronic skin condition that does not require systemic therapy

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

          -  Participants with celiac disease controlled by diet alone

          -  Participants with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone > 10 mg daily, cyclophosphamide, azathioprine, methotrexate, thalidomide,
             and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1.
             However, the use of inhaled corticosteroids and mineralocorticoids (e.g.,
             fludrocortisone) for participants with orthostatic hypotension or adrenocortical
             insufficiency is allowed.

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

          -  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 AEs or compromise the ability of the participant to give written
             informed consent

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), hepatitis B (known positive hepatitis B surface antigen
             [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive human
             immunodeficiency virus [HIV] 1/2 antibodies). Participants with a past or resolved
             hepatitis B (HBV) infection (defined as the presence of hepatitis B core antibody
             [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C
             (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

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

          -  Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
             study regardless of treatment arm assignment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of intervention as defined by number of participants with Dose Limiting Toxicities (DLT) between first dose of Durvalumab and 30 days following completion of radiotherapy.
Time Frame:Up to 30 days following end of treatment
Safety Issue:
Description:Safety of intervention as defined by number of participants with DLT's between first dose of Durvalumab and 30 days following completion of radiotherapy. This is defined as 0 of 3 or 1 of 6 participants having no DLT of either Durvalumab or RT. DLT for RT defined as: Grade 4-5 non-hematologic serious adverse events (SAEs) considered by the Investigators to be probably or definitely related to protocol treatment. Grade 3 or higher cardiac adverse events (e.g. severely symptomatic congestive heart failure (CHF), myocarditis, pericardial effusion, myocardial infarction, symptomatic arrhythmia) considered by the Investigators to be probably or definitely related to protocol treatment. Grade 3 or higher pulmonary adverse events (e.g. dyspnea/pneumonitis) considered by the Investigators to be probably or definitely related to protocol treatment and not responsive to steroids. Failure to receive at least 54

Secondary Outcome Measures

Measure:Feasibility of intervention defined by number of participants receiving full course of RT treatment and minimum of two doses of Durvalumab
Time Frame:Up to 30 days following end of treatment
Safety Issue:
Description:Feasibility of intervention is defined as a participant receiving the entire course of prescribed RT as well as having received a minimum of two doses of Durvalumab.
Measure:Number of participants with Adverse Events according to CTCAE v5.0
Time Frame:Up to 30 days following end of treatment
Safety Issue:
Description:All toxicities will be graded according to NCI CTCAE, Version 5.0. See Adverse Events section.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • Durvalumab
  • PARTICLE-D

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