Clinical Trials /

Phase Ib Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Non-small Lung Cancer (NSCLC) With Dual Immune Checkpoint Inhibition

NCT03275597

Description:

This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition (DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease sites followed by combination of durvalumab and tremelimumab for patients for whom the goal is ablating all known sites of disease. We anticipate that for many patients this will be the first line-therapy. Patients who have received prior-platinum-based chemotherapy and/or any line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib Study of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Non-small Lung Cancer (NSCLC) With Dual Immune Checkpoint Inhibition
  • Official Title: Comprehensive Stereotactic Body Radiotherapy (SBRT) to All Sites of Oligometastatic Non-small Cell Lung Cancer (NSCLC) Combined With Durvalumab (MEDI4736) and Tremelimumab Dual Immune Checkpoint Inhibition.

Clinical Trial IDs

  • ORG STUDY ID: UW17003
  • SECONDARY ID: P30CA014520
  • NCT ID: NCT03275597

Conditions

  • Non-small Cell Lung Cancer
  • Non-small Cell Lung Cancer Stage IV

Interventions

DrugSynonymsArms
Durvalumab1428935-60-7, D10808SBRT followed by Durvalumab+Tremelimumab
Tremelimumab745013-59-6, QEN1X95CIXSBRT followed by Durvalumab+Tremelimumab

Purpose

This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition (DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease sites followed by combination of durvalumab and tremelimumab for patients for whom the goal is ablating all known sites of disease. We anticipate that for many patients this will be the first line-therapy. Patients who have received prior-platinum-based chemotherapy and/or any line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.

Trial Arms

NameTypeDescriptionInterventions
SBRT followed by Durvalumab+TremelimumabExperimentalTherapeutic Interventions Stereotactic Body Radiotherapy (SBRT) to all sites of disease between 30 and 50 Gy in five fractions administered over two weeks. Investigational Product(s), Dose, and Mode of Administration: to begin 7 days (+/- 1 day) after radiation Durvalumab 1500 mg via infusion Q4W (equivalent to 20 mg/kg Q4W) until disease progression in patients > 30 kg Tremelimumab 75 mg via infusion Q4W (equivalent to 1 mg/kg Q4W) for up to 4 doses/cycles in patients >30 kg Weight-based dosing utilized for patients ≤30 kg; durvalumab 20 mg/kg Q4W and tremelimumab 1 mg/kg Q4W
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  • Patients with histologically or cytologically confirmed stage IV NSCLC not amenable
             to curative surgery or radiation

               -  Patients may have had prior chemotherapy or be chemotherapy naïve

               -  Patients must have tumors that lack sensitizing EGFR mutation (e.g. exon 19
                  deletion or exon 21 L858R) or ALK rearrangement. If a patient has squamous
                  histology, then EGFR and ALK testing is not required.

               -  No prior treatment with cancer immunotherapy including, but not limited to, other
                  anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 anti-
                  (PD-L2) antibodies, excluding therapeutic anticancer vaccines.

               -  Patients will have 6 or less extracranial sites, which can safely receive SBRT
                  between 30 - 50 Gy in 5 fractions. A site may have multiple tumor lesions within
                  it as long as the gross tumor volume (GTV) of the site is 8 cm or less and can be
                  covered in an acceptable SBRT field determined by the PI. All gross disease must
                  be amenable to treatment with SBRT, as allowable per normal tissue constraints.
                  Patients will not have had any prior radiation therapy significantly overlapping
                  a tumor site to be treated.

               -  Patients must have evaluable disease, as defined by RECIST 1.1.

               -  World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
                  performance status of 0 or 1 at enrollment

               -  Life expectancy of > 12 weeks

               -  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.

               -  Patients treated metastatic lesions to the brain may be enrolled after completing
                  stereotactic radiosurgery (may enroll 14 days after treatment) or whole brain
                  radiation (may enroll 14 days after treatment) and being weaned off
                  corticosteroids for 14 days prior to treatment.

               -  Adequate normal organ and marrow function as defined below:

               -  Hemoglobin ≥ 9.0 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)

               -  Platelet count ≥ 100 x 109/L (>100,000 per mm3)

               -  Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not
                  apply for patients with confirmed Gilbert's syndrome, who will be allowed in
                  consultation with their physician.

               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN unless liver metastases are present, in which
                  case ALT and AST must be ≤ 5x ULN

               -  Serum creatinine CL ≥ 50 mL/min

               -  Female subject of childbearing potential should have a negative urine or serum
                  pregnancy prior to receiving the first study treatment. If the urine test is
                  positive or cannot be confirmed as negative, a serum pregnancy test will be
                  required

               -  Female subjects of childbearing potential should be willing to use 1 method of
                  highly effective birth control, 2 methods of effective birth control, be
                  surgically sterile, or abstain from heterosexual activity for the course of the
                  study through 180 days after the last dose of study medication. Subjects of
                  childbearing potential are those who have not been surgically sterilized or have
                  not been free from menses for > 1 year.

               -  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 oophorectomy with last menses >1 year ago, had
                  chemotherapy-induced menopause with > 1 year interval since last menses, or
                  underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

               -  Patient must be willing and able to provide written informed consent for the
                  trial.

        Exclusion Criteria:

          -  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

               -  Previous enrolment in the present study

               -  Mixed small-cell lung cancer and sarcomatoid variant NSCLC histology

               -  Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
                  treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
                  (eg, hormone replacement therapy) is acceptable.

               -  Major surgical procedure (as defined by the Investigator) within 14 days prior to
                  the start of study treatment.

               -  Patients with untreated spinal cord compression. Patients with spinal cord
                  compression may be enrolled if stable after completing surgery (may enroll 14
                  days after surgery) or radiation (may enroll 14 days after radiation) and must be
                  off corticosteroids for at least 14 days prior to the start of study treatment.

               -  Patients with untreated brain metastasis. Patients with metastatic lesions to the
                  brain may be enrolled after completing stereotactic radiosurgery or whole brain
                  radiation (may enroll 14 days after radiation and must be off corticosteroids for
                  at least 14 days prior to the start of study treatment.

               -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
                  anti-CTLA4 inhibitor including tremelimumab

               -  Patients with a known targetable EGFR mutation or ALK rearrangement

               -  History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease ≥2 years

               -  Non-metastatic prostate adenocarcinoma, or treated superficial non-invasive
                  bladder cancer

               -  Adequately treated carcinoma in situ without evidence of disease (eg, cervical
                  cancer in situ)

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

               -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
                  endocrine therapy, targeted therapy, biologic therapy, tumor embolization,
                  monoclonal antibodies, other investigational agent) ≤ 14 days of registration

               -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470
                  ms. Abnormality must be confirmed on 3 ECGs.

               -  Current or prior use of immunosuppressive medication within 14 days before the
                  first dose of durvalumab or tremelimumab

        The following are exceptions to this criterion:

          -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,
             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 (eg, CT scan premedication)

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis with the
             exception of diverticulosis, celiac disease or other serious gastrointestinal chronic
             conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
             syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease,
             rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the
             start of treatment. The following are exceptions to this criterion:

          -  Patients with vitiligo or alopecia,

          -  Grave's disease,

          -  Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement,

          -  Psoriasis not requiring systemic treatment (within the past 2 years),

          -  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

          -  History of active primary immunodeficiency

          -  History of allogeneic organ transplant

          -  Active infection, including tuberculosis (clinical evaluation), hepatitis B, hepatitis
             C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). Active
             hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg)
             result. Patients with a past or resolved HBV infection (defined as the presence of
             hepatitis B core antibody 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).

          -  History of leptomeningeal carcinomatosis

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

          -  Any condition or uncontrolled intercurrent illness that, in the opinion of the
             Investigator, would interfere with the evaluation of IP or interpretation of patient
             safety or study results, including, but not limited to, ongoing or active infection,
             symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
             limit compliance with study requirement, substantially increase risk of incurring AEs
             from durvalumab or tremelimumab, or compromise the ability of the patient to give
             written informed consent

          -  Subjects with uncontrolled seizures.

          -  Female patients who are pregnant or breast-feeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 180 days after the last dose of durvalumab and tremelimumab combination
             therapy or 90 days after the last dose of durvalumab monotherapy.

          -  History of hypersensitivity to IP or comparator agents

          -  History of medically diagnosed pneumonitis or interstitial lung disease
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03
Time Frame:Up to 3 years
Safety Issue:
Description:Toxicities will be summarized by type and severity in tabular format. Toxicity rates (grade 2, grade 3, grade 4, grade ≥ 2, grade ≥ 3, etc.) will be calculated and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method.

Secondary Outcome Measures

Measure:Progression Free Survival assessed with RECIST 1.1 tumor assessments
Time Frame:Up to 4 years
Safety Issue:
Description:Progression-free survival (PFS) will be defined as the difference (in months) between the date of study enrollment and the date of disease progression or death due to any cause. PFS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median PFS. PFS assessed with RECIST 1.1 tumor assessments. The effect of DCI with durvalumab and tremelimumab will be compared against historical controls for a 95% CI and p-value.
Measure:Overall Survival assessed with RECIST 1.1 tumor assessments
Time Frame:Up to 4 years
Safety Issue:
Description:Overall survival (OS) will be defined as the difference (in months) between the date of study enrollment to the date death due to any cause. OS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median OS. The effect of DCI with durvalumab tremelimumab will be compared against historical controls for a 95% CI and p-value.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Wisconsin, Madison

Last Updated

October 10, 2017