| Eligibility |
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed non-small cell lung
cancer (cohort 1) or colorectal cancer (cohort 2)
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
conventional techniques or as >= 10 mm (>= 1.5 cm) with spiral computed tomography
(CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Patients in both cohorts must have progressive disease following prior therapy;
specifically:
- Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical disease
progression during previous treatment with systemic PD-1 directed therapy and/or
have been deemed not to derive clinical benefit from PD-1 directed treatment;
this includes patients who demonstrated an initial response and subsequent
progression; no prior treatment with chemotherapy or targeted agents are
required; intervening therapy is allowed between previous PD-1 directed treatment
and there is no required interval from prior PD-1 treatment required; PD-1
directed treatment includes treatment with antibodies targeting the PD-1 receptor
such as pembrolizumab or nivolumab, as well as PD-L1 targeted antibodies such as
MEDI4736 (durvalumab), atezolizumab and avelumab; these agents may have been
administered as part of a clinical trial
- Cohort 2 (colorectal cancer): Patients must have progressed on >= one-line
chemotherapy
- At least 21 days must have elapsed from prior systemic therapy (chemotherapy or
radiation)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
and life expectancy greater than 6 months; furthermore, enrollment of patients with
greater than 10 measurable lesions is discouraged
- Patients must have normal organ and marrow function independent of transfusion for at
least 7 days prior to screening and independent of growth factor support for at least
14 days prior to screening
- Hemoglobin (Hgb) >= 9 g/dl
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x normal institutional limits; this will not apply to patients
with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia
[predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or
hepatic pathology), who will be allowed in consultation with their physician
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
= < 2.5 x institutional upper limit of normal; for patients with hepatic metastases,
ALT and AST =< 5 x ULT
- Measured creatinine clearance (CL) > 40 mL/min OR calculated creatinine clearance (CL)
> 40 mL/min as determined by Cockcroft-Gault (using actual body weight)
- Patients must have at least one lesion that has not previously been irradiated (and is
not within a previously radiated field) and for which palliative radiation is
potentially indicated and could be safely delivered at the radiation doses specified
in this protocol; this lesion must not be the only measurable lesion so that it is
still possible to determine the response rate outside of the radiation treatment
field; this lesion must not be within the central nervous system (CNS) (brain or
spinal cord) or requiring urgent or emergent palliative radiation given the timing of
radiation specified on this protocol; furthermore, this lesion:
- For cohort 1 (NSCLC cohort) - the lesion to be irradiated must be in the lung,
lymph nodes, adrenal gland or liver
- For cohort 2 (colorectal cohort) - the lesion to be irradiated must be in the
liver
- The effects of MEDI4736 and tremelimumab on the developing human fetus are unknown;
for this reason and because radiation is known to be teratogenic, evidence of
post-menopausal status or negative urinary or serum pregnancy test for female
pre-menopausal patients is required; 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)
- Females of childbearing potential who are sexually active with a non sterilized male
partner must use at least 1 highly effective method of contraception from the time of
screening and must agree to continue using such precautions for 180 days after the
last dose of durvalumab + tremelimumab combination therapy or 90 days after the last
dose of durvalumab monotherapy; non-sterilized male partners of a female patient must
use male condom plus spermicide throughout this period; cessation of birth control
after this point should be discussed with a responsible physician; not engaging in
sexual activity for the total duration of the drug treatment and the drug washout
period is an acceptable practice; however, periodic abstinence, the rhythm method, and
the withdrawal method are not acceptable methods of birth control; female patients
should also refrain from breastfeeding throughout this period
- Non-sterilized males who are sexually active with a female partner of childbearing
potential must use a male condom plus spermicide from screening through 180 days after
receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days
after receipt of the final dose of durvalumab monotherapy; not engaging in sexual
activity is an acceptable practice; however, occasional abstinence, the rhythm method,
and the withdrawal method are not acceptable methods of contraception; male patients
should refrain from sperm donation throughout this period
- Female partners (of childbearing potential) of male patients must also use a highly
effective method of contraception throughout this period
- Highly effective methods of contraception, defined as one that results in a low
failure rate (ie, less than 1% per year) when used consistently and correctly are
described in the table below; note that some contraception methods are not considered
highly effective (e.g. male or female condom with or without spermicide; female cap,
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine
device; progestogen-only oral hormonal contraceptive pills where inhibition of
ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is
considered highly effective]; and triphasic combined oral contraceptive pills)
- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately
- Ability of a patient or a Legally Authorized Representative (LAR) to understand and
the willingness to sign a written informed consent document
- Body weight > 30 kg
- Must have a life expectancy of at least 12 weeks
- Cohort 1 (NSCLC cohort)
- Ability to undergo a fresh tumor biopsy for the purpose of screening for this
clinical trial (including able and willing to give valid written consent) to
ability or to provide an available archival tumor sample taken less than 3 months
prior to study enrollment (and not obtained prior to progression on a PD-1/PD-L1
inhibitor) if a fresh tumor biopsy is not feasible with an acceptable clinical
risk; tumor lesions used for fresh biopsies should be the same lesions to be
irradiated when possible and should not be the same lesions used as Response
Evaluation Criteria in Solid Tumors (RECIST) target lesions, unless there are no
other lesions accessible; additional, optional archival tumor tissue is also
requested from before the prior PD-1 directed therapy
- Cohort 2 (colorectal cohort)
- Ability to undergo a fresh tumor biopsy for the purpose of screening for this
clinical trial (including able and willing to give valid written consent) to
ability or to provide an available archival tumor sample taken less than 3 months
prior to study enrollment if a fresh tumor biopsy is not feasible with an
acceptable clinical risk; tumor lesions used for fresh biopsies should be the
same lesions to be irradiated when possible and should not be the same lesions
used as RECIST target lesions, unless there are no other lesions accessible
- Microsatellite stable (MSS) tumor as documented by either:
- Immunohistochemistry (IHC) testing that does not suggest loss of MLH-1,
MSH-2, PMS2 or MSH6
- Polymerase chain reaction (PCR) testing that does not suggest microsatellite
instability (MSI)
Exclusion Criteria:
- Patients who have had systemic (chemotherapy, biologic therapy or radiotherapy) within
3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- Receipt of prior radiotherapy or condition for any reason that would contribute
radiation dose that would exceed tolerance of normal tissues, at the discretion of the
treating physician
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1)
- Patients who are receiving any other investigational agents
- Patients with untreated brain metastases, spinal cord compression, or leptomeningeal
carcinomatosis should be excluded from this clinical trial; patients whose brain
metastases have been treated may participate provided they show radiographic stability
(defined as 2 brain images, both of which are obtained after treatment to the brain
metastases; these imaging scans should both be obtained at least four weeks apart and
show no evidence of intracranial progression); in addition, any neurologic symptoms
that developed either as a result of the brain metastases or their treatment must have
resolved or be stable either, without the use of steroids, or are stable on a steroid
dose of =< 10 mg/day of prednisone or its equivalent (and anti-convulsants) for at
least 14 days prior to the start of treatment
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to tremelimumab and MEDI4736 or previous toxicity attributed to MEDI4736
or other PD-1 or PD-L1 directed therapy that led to drug discontinuation
- Prior exposure to immune-mediated therapy, including durvalumab and tremelimumab,
except for anti-PD-1 or anti-PD-L1 therapy (including durvalumab) in NSCLC patients;
this includes anti-CTLA-4 agents (prior treatment with these agents is NOT allowed in
either cohort) and, excludes therapeutic anticancer vaccines, excluding therapeutic
anticancer vaccines; exposure to other investigational agents may be permitted after
discussion with the study principal investigator (PI)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because MEDI4736 (durvalumab),
tremelimumab are immune checkpoint inhibitors with the potential for teratogenic or
abortifacient effects, as is radiation therapy; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with MEDI4736(durvalumab), tremelimumab and radiation, breastfeeding should be
discontinued if the mother is treated with MEDI4736(durvalumab), tremelimumab and
radiation
- 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 or 180 days after
the last dose of durvalumab + tremelimumab combination therapy, whichever is later
- Human immunodeficiency virus (HIV)-positive patients are ineligible; appropriate
studies will be undertaken in patients receiving combination antiretroviral therapy
when indicated
- Any concurrent chemotherapy, immune therapy, biologic, hormonal therapy for cancer
treatment
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of their assigned IP; 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 pre-medication for hypersensitivity reactions (e.g., CT scan
pre-medication)
- Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of IP; Note: local surgery of isolated lesions for palliative intent is
acceptable
- History of allogeneic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease, diverticulitis [with the exception of diverticulosis];
sarcoidosis syndrome, or other serious gastrointestinal [GI] chronic conditions
associated with diarrhea; systemic lupus erythematosus; Wegener syndrome
[granulomatosis with polyangiitis]; myasthenia gravis; Graves disease; rheumatoid
arthritis; hypophysitis; uveitis, sarcoidosis syndrome, etc.) within the past 3 years
prior to the start of treatment; the following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement or psoriasis not requiring systemic treatment
- 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 another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease >= 5
years before the first dose of study drug 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 (e.g., cervical
cancer in situ)
- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from
electrocardiograms (ECGs) using Fridericia's correction; abnormal ECGs should be
repeated
- History of active primary immunodeficiency
- Known history of previous clinical diagnosis of tuberculosis
- Active infection including hepatitis B (known positive hepatitis B virus [HBV] surface
antigen [HBsAg]) result or, 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 (HCV) antibody are eligible
only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA); negative
serologies documented over the past year are sufficient evidence of this
- Receipt of live, attenuated vaccine within 30 days prior to the first dose of
investigational treatment; Note: patients, if enrolled, should not receive live
vaccine during the study and up to 30 days after the last dose of investigational
treatment
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of the investigational treatment or interpretation of patient safety or
study results
- Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) 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 treatment with durvalumab or
tremelimumab may be included only after consultation with the study physician
- Cohort 1 (NSCLC cohort)
- In regards to administration of prior anti-PD-1 or anti PD-L1 antibodies, a
patients:
- Must not have experienced a toxicity that led to permanent discontinuation
of prior immunotherapy
- All adverse events (AEs) while receiving prior immunotherapy must have
completely resolved or resolved to baseline prior to screening for this
study
- Must not have experienced a >= grade 3 immune related AE or an immune
related neurologic or ocular AE of any grade while receiving prior
immunotherapy; NOTE: subjects with endocrine AE of =< grade 2 are permitted
to enroll if they are stably maintained on appropriate replacement therapy
and are asymptomatic
- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence
of an AE if re-challenged, and not currently require maintenance doses of >
10 mg prednisone or equivalent per day
- Eligibility for Food and Drug Administration (FDA)-approved agents targeting the
EGFR, ROS1 or ALK pathway, which should be evaluated as per standard of care;
exceptions to this requirement may be considered on a case-by-case basis by the
principal investigator if the patient was previously treated with another
targeted agent
|
