Description:
This randomized phase I/II trial studies the side effects and best dose of pembrolizumab when
given together with stereotactic body radiation therapy or non-stereotactic wide-field
radiation therapy (conventional radiation therapy) and to see how well they work in treating
patients with non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as
pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays to
kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special
equipment to position a patient and deliver radiation to tumors with high precision. This
method can kill tumor cells with fewer doses over a shorter period and cause less damage to
normal tissue. Giving pembrolizumab together with radiation therapy may kill more tumor
cells.
Title
- Brief Title: Pembrolizumab and Stereotactic Body Radiation Therapy or Non-Stereotactic Wide-Field Radiation Therapy in Treating Patients With Non-small Cell Lung Cancer
- Official Title: Phase I/II Trial of MK-3475 and Hypofractionated Stereotactic Radiation Therapy in Patients With NSCLC
Clinical Trial IDs
- ORG STUDY ID:
2014-1020
- SECONDARY ID:
NCI-2015-01505
- SECONDARY ID:
2014-1020
- NCT ID:
NCT02444741
Conditions
- Malignant Solid Neoplasm
- Metastatic Lung Non-Small Cell Carcinoma
- Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
Drug | Synonyms | Arms |
---|
Pembrolizumab | Keytruda, Lambrolizumab, MK-3475, SCH 900475 | Group I, Phase I (pembrolizumab + SBRT) |
Purpose
This randomized phase I/II trial studies the side effects and best dose of pembrolizumab when
given together with stereotactic body radiation therapy or non-stereotactic wide-field
radiation therapy (conventional radiation therapy) and to see how well they work in treating
patients with non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as
pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
the ability of tumor cells to grow and spread. Radiation therapy uses high-energy x-rays to
kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special
equipment to position a patient and deliver radiation to tumors with high precision. This
method can kill tumor cells with fewer doses over a shorter period and cause less damage to
normal tissue. Giving pembrolizumab together with radiation therapy may kill more tumor
cells.
Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the safety and toxicity profile of intravenous MK-3475 (pembrolizumab)
administered in combination with stereotactic body radiation therapy (SBRT) targeting 1-4
liver or thoracic lesion(s) in patients with metastatic non-small cell lung cancer (NSCLC).
(Phase I) II. To evaluate the safety and toxicity profile of intravenous MK-3475 administered
in combination with non-stereotactic wide-field radiation therapy (WFRT) targeting 1-4 liver
or thoracic lesion(s) in patients with metastatic NSCLC. (Phase I) III. To determine the
maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of MK-3475 and SBRT
combination therapy. (Phase I) IV. To determine the maximum tolerated dose (MTD) and dose
limiting toxicities (DLTs) of MK-3475 and WFRT combination therapy. (Phase I) V. To determine
the rate of out-of-field objective responses (either complete response [CR] or partial
response [PR]) of the non-irradiated disease sites. (Phase II)
SECONDARY OBJECTIVE:
I. To determine whether the addition of radiation therapy (XRT) to MK-3475 can improve the
progression free survival (PFS) rate compared to MK-3475 alone. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of pembrolizumab followed by a phase II
study.
PHASE I: Patients are assigned to 1 of 2 treatment groups.
GROUP I: Patients who exhibit a lung lesion of size and location amenable to SBRT receive
pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive SBRT in 4
fractions daily on days 2-5 or either intensity modulated radiation therapy (IMRT), proton
beam radiation therapy (PBRT), or 3 dimensional conformation radiation therapy (3D-CRT) in 15
fractions total concurrent with pembrolizumab administration on days 1-19. Treatment repeats
every 21 days for up to 16 courses in the absence of disease progression or unacceptable
toxicity.
GROUP II: Patients who exhibit a lung lesion of size or location not amenable to SBRT, but
amenable to WFRT receive pembrolizumab as in Group I and either IMRT, PBRT, or 3D-CRT in 15
fractions total concurrent with pembrolizumab administration.
PHASE II: Patients for whom SBRT is recommended are randomized to Group 1 or 2, patients for
whom conventional radiation therapy is recommended are randomized to Group 3 or 4, and
patients with lesions amenable to SBRT or WFRT are assigned to Group 5.
GROUP I: Patients who exhibit a lung lesion with size and location amenable to SBRT receive
pembrolizumab IV on day 1 and SBRT on days 44-47 or IMRT, PBT, or 3D-CRT on days 43-61.
Treatment with pembrolizumab repeats every 21 days for up to 16 courses in the absence of
disease progression or unacceptable toxicity.
GROUP II: Patients who exhibit a lung lesion with size and location amenable to SBRT receive
pembrolizumab IV as in Group I without XRT. At the first planned efficacy evaluation (5
weeks), patients exhibiting progressive disease (PD) are treated with SBRT concurrent with
the remaining cycles of pembrolizumab. In the event that lesion size has progressed to the
point where the attending physician no longer considers SBRT safe, then the patient will be
salvaged with IMRT, PBRT, or 3D-CRT and analyzed as part of the fourth treatment group.
GROUP III: Patients who exhibit a lung lesion with size and location not amenable to SBRT,
but amenable to WFRT receive pembrolizumab IV as in Group I and IMRT, PBRT, or 3D-CRT on days
43-61.
GROUP IV: Patients who exhibit a lung lesion with size and location not amenable to SBRT, but
amenable to WFRT receive pembrolizumab IV as in Group I without XRT. The decision on when to
start XRT will be assessed first at week 5 (after the second dose of pembrolizumab). If a
patient has PD based on immune response related criteria (irRC) then XRT will be delivered
after the third dose of pembrolizumab, while patients with stable disease (SD) or PR will not
start XRT and will continue to be followed. These patients will then have follow up computed
tomography (CT) scans 5 weeks after course 3 three and then approximately every 3 months for
the remainder of the trial; any patient at this point with PD will then have XRT delivered
with the sixth dose of pembrolizumab.
GROUP V: Patients with lesions amenable to SBRT or WFRT receive pembrolizumab IV as in Group
I. Patients also receive either IMRT, PBRT, or 3D-CRT in 15 fractions to the primary lesions
and low dose radiation therapy to other lesions on days 43-61 or SBRT in 4 fractions to
primary lesions and low dose radiation therapy to other lesions on days 44-47.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks.
Trial Arms
Name | Type | Description | Interventions |
---|
Group I, Phase I (pembrolizumab + SBRT) | Experimental | Patients who exhibit a lung lesion of size and location amenable to SBRT receive pembrolizumab IV over 30 minutes on day 1. Patients also receive SBRT in 4 fractions daily on days 2-5 or either IMRT, PBRT, or 3D-CRT in 15 fractions total concurrent with pembrolizumab administration on days 1-19. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity. | |
Group I, Phase II (pembrolizumab + SBRT) | Experimental | Patients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV on day 1 and SBRT on days 44-47 or IMRT, PBT, or 3D-CRT on days 43-61. Treatment with pembrolizumab repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity. | |
Group II, Phase I (pembrolizumab + IMRT, PBRT or 3D-CRT) | Experimental | Patients who exhibit a lung lesion of size or location not amenable to SBRT, but amenable to WFRT receive pembrolizumab as in Group I and either IMRT, PBRT, or 3D-CRT in 15 fractions total on days 1-19 concurrent with pembrolizumab administration. | |
Group II, Phase II (pembrolizumab + XRT upon PD) | Experimental | Patients who exhibit a lung lesion with size and location amenable to SBRT receive pembrolizumab IV as in Group I without XRT. At the first planned efficacy evaluation (5 weeks), patients exhibiting PD are treated with SBRT concurrent with the remaining cycles of pembrolizumab. In the event that lesion size has progressed to the point where the attending physician no longer considers SBRT safe, then the patient will be salvaged with IMRT, PBRT, or 3D-CRT and analyzed as part of the fourth treatment group. | |
Group III, Phase II (pembrolizumab + IMRT, PBRT, or 3D-CRT) | Experimental | Patients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I and IMRT, PBRT, or 3D-CRT on days 43-61. | |
Group IV, Phase II (pembrolizumab + XRT upon PD) | Experimental | Patients who exhibit a lung lesion with size and location not amenable to SBRT, but amenable to WFRT receive pembrolizumab IV as in Group I without XRT. The decision on when to start XRT will be assessed first at week 5 (after the second dose of pembrolizumab). If a patient has PD based on irRC then XRT will be delivered after the third dose of pembrolizumab, while patients with SD or PR will not start XRT and will continue to be followed. These patients will then have follow up CT scans 5 weeks after course 3 and then approximately every 3 months for the remainder of the trial; any patient at this point with PD will then have XRT delivered with the sixth dose of pembrolizumab. | |
Group V, Phase II (low dose radiation therapy) | Experimental | Patients with lesions amenable to SBRT or WFRT receive pembrolizumab IV as in Group I. Patients also receive either IMRT, PBRT, or 3D-CRT in 15 fractions to the primary lesions and low dose radiation therapy to other lesions on days 43-61 or SBRT in 4 fractions to primary lesions and low dose radiation therapy to other lesions on days 44-47. | |
Eligibility Criteria
Inclusion Criteria:
- Pathologically confirmed non-small lung cancer; for patients in group 5, any solid
tumor histology to be included
- Stage IV metastatic disease (only during the phase II)
- At least one thoracic or liver lesion amenable to radiation, for group 5 we need one
area that can safely receive SBRT or WFRT, not restricted to lung or liver sites
- At least one additional non-contiguous lesion to the irradiated lesion amenable to
radiographic evaluation
- Be willing and able to provide written informed consent/assent for the trial
- Have measurable disease based on immune related response criteria (irRC) criteria
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale
- Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 28 days prior to study
registration up to the first dose of study drug)
- Platelets >= 100,000 /mcL (performed within 28 days prior to study registration up to
the first dose of study drug)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 28 days prior to study
registration up to the first dose of study drug)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) or measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or calculated creatinine clearance [CrCl]) or >= 60 mL/min for subject with
creatinine levels > 1.5 X institutional ULN (creatinine clearance should be calculated
per institutional standard) (performed within 28 days prior to study registration up
to the first dose of study drug)
- Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 28 days prior to study registration up to
the first dose of study drug)
- Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) =< 2.5 X ULN
or =< 5 X ULN for subjects with liver metastases (performed within 28 days prior to
study registration up to the first dose of study drug)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial prothrombin time
(PTT) is within therapeutic range of intended use of anticoagulants (performed within
28 days prior to study registration up to the first dose of study drug)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants (performed within 28 days prior to study registration up to the
first dose of study drug)
- Patients with brain metastasis will be included as long as they are free of neurologic
symptoms related to metastatic brain lesions and who do not require or receive
systemic corticosteroid therapy in the 14 days prior to beginning MK-3475 therapy
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; 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 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 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
- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy
- We will allow XRT prior to study entry to other sites, with no washout period, allowed
prior to study entry as long as at least one measurable sites of disease is kept
unirradiated
Exclusion Criteria:
- Is currently participating in or has participated in a study of an investigational
agent (except glutamine) or using an investigational device within 4 weeks of the
first dose of treatment or 5 half lives, whichever is shorter
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment; unless the steroid therapy is for physiological replacement
- Has a diagnosis of active scleroderma, lupus, or other autoimmune disease which by the
opinion of the treating radiation oncologist precludes safe radiation therapy
- Has had prior radiation therapy to all available thoracic and liver lesions such that
additional radiation therapy is unsafe by the opinion of the treating radiation
oncologist
- Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, which ever is
shorter, prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to
study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse
events due to a previously administered agent
- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment
- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; subjects with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; subjects that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; subjects with hypothyroidism stable on hormone replacement or
Sjogren's syndrome will not be excluded from the study
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy or hospital admission
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B virus HBsAg surface protein antigen
[HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
[qualitative] is detected)
- Has received a live vaccine within 30 days prior to the first dose of trial treatment
- Symptomatic brain metastasis
- Has experienced a dose limiting toxicity on treatment with either prior radiation or
anti programmed cell death 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1)
inhibitor therapy
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Disease response, according to immune related response criteria (Phase I/II) |
Time Frame: | Beginning 3 months after initiation of treatment |
Safety Issue: | |
Description: | Treatment success will be defined as radiographic complete response or partial response measured using Pearson chi-squared or Fisher exact tests. |
Secondary Outcome Measures
Measure: | Progression-free survival (Phase II) |
Time Frame: | From the time of enrollment to first evidence of progressive disease, assessed at 3 months after treatment initiation |
Safety Issue: | |
Description: | Analysis conducted using Kaplan-Meier method. At the discretion of the investigators, multivariate Cox regression will be done to adjust for (among other factors): number of metastatic disease sites, number of prior treatments, primary cancer histology, age, pre-treatment Karnofsky performance scale, and Royal Marsden score. |
Measure: | Overall survival |
Time Frame: | Receipt of the first pembrolizumab dose to death, assessed up to 5 years |
Safety Issue: | |
Description: | Analysis conducted using Kaplan-Meier method, with comparisons regarding overall survival made via the log-rank test. At the discretion of the investigators, multivariate Cox regression will be done to adjust for (among other factors): number of metastatic disease sites, number of prior treatments, primary cancer histology, age, pre-treatment Karnofsky performance scale, and Royal Marsden score. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | M.D. Anderson Cancer Center |
Last Updated
March 24, 2021