PRIMARY OBJECTIVE:
I. To determine the safety of adding MEDI4736 (durvalumab) to standard chemotherapy regimens.
SECONDARY OBJECTIVES:
I. Determine the changes that occur in the immune microenvironment in response to
chemotherapy and assess how these changes alter the pharmacodynamic effects of a checkpoint
inhibitor.
II. Investigate whether the response to immunotherapy correlates with patients' genetic
aberrations and/or the activation status of tumor-infiltrating and circulating T cells.
III. Explore the relationship between immune status of the tumor and overall tumor mutational
load.
IV. Assess preliminary antitumor activity of the MEDI4736 (durvalumab) and chemotherapy
combinations.
OUTLINE: Patients are assigned to 1 of 7 arms.
ARM I: Patients receive durvalumab intravenously (IV) over 60 minutes on days 1 and 15 of
cycles 1 and 2 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
ARM II: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15
and durvalumab IV over 60 minutes on days 8 and 22 of cycles 1 and 2 and day 8 of subsequent
cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
ARM III: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on
day 1 and durvalumab IV over 60 minutes on days 8 and 22 of cycles 1 and 2 and day 1 of
subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
ARM IV: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14, and
durvalumab IV over 60 minutes on days 8 of cycle 1, day 8 and 15 of cycle 2, day 8 of cycles
3, and day 1 of subsequent cycles. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
ARM V: Patients receive carboplatin IV over 30-60 minutes on day 1 and durvalumab IV over 60
minutes on day 8 of cycle 1, days 8 and 15 of cycle 2, day 8 of cycles 3, and day 1 of
subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
ARM VI: Patients receive paclitaxel IV over 60 minutes on day 1 and durvalumab IV over 60
minutes on day 8 of cycle 1, days 8 and 15 of cycle 2, day 8 of cycles 3, and day 1 of
subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
ARM VII: Patients receive nab-paclitaxel IV over 30 minutes on day 1 and durvalumab IV over
60 minutes on day 8 of cycle 1, days 8 and 15 of cycle 2, day 8 of cycles 3, and day 1 of
subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up monthly for 3 months.
Inclusion Criteria:
- Patients with histologically documented metastatic or locally advanced (not amenable
to surgery) solid tumors whose disease has progressed following at least one line of
standard therapy and/or no standard of treatment exists that has been shown to prolong
survival.
- If anti-PD-1 or one of the 6 chemotherapy agents is standard-of-care, prior
therapy with the agent would not be required.
- Patient must have tumor amenable to biopsy and be willing to undergo a tumor biopsy.
- Flash frozen tissue collected as part of another study or from a procedure
performed due to medical necessity may be acceptable as the baseline sample if
the samples were collected within 3 months prior to registration and the patient
has not received any investigational or targeted treatment since that time.
- 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) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT)
scan.
- Patients with bone metastases or hypercalcemia on intravenous bisphosphonate
treatment, denosumab, or similar agents are eligible to participate and may continue
this treatment. Patients with prostate cancer may continue luteinizing
hormone-releasing hormone (LHRH) agonists or antagonists.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Absolute neutrophil count >= 1,000/uL (mcL).
- Platelets >= 100,000/uL (mcL).
- Total bilirubin < 1.5 x institutional upper limit of normal.
- This will not apply to patients with confirmed Gilbert syndrome (persistent or
recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
hemolysis or hepatic pathology), who will be allowed only at the discretion of
the principal investigator (PI), study chair or their designee.
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal, or up to 5 x upper limit of normal (ULN)
if liver metastases are present.
- Calculated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula
- Any prior systemic therapy (including checkpoint inhibitors), or major surgery must
have been completed >= 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) or 5
half-lives of the agent, whichever is shorter, prior to enrollment on protocol, and
toxicity from prior treatment must have recovered to eligibility levels. Radiation
therapy must have been completed >= 1 week prior to starting treatment. Radiofrequency
ablation (RFA) of localized lesions should have been performed >= 1 week prior to
starting treatment. All radiation-related toxicity must have resolved to < grade 2.
- Palliative radiotherapy is permitted between disease progression on Arm 1 and
crossover to a combination therapy arm (Arms 2-7), provided there is a washout
period of >= 1 week and any toxicity from radiation has resolved to < grade 2
- Patients on any arm may receive palliative radiotherapy or loco-regional ablative
therapy and remain on study, provided the radiation is not delivered to the
target lesion and the patient does not have tumor progression by Response
Evaluation Criteria in Solid Tumors (RECIST)
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon-alpha or interleukin-2) must have been completed at least 6 weeks before
the first dose of MEDI4736 (durvalumab).
- Body weight > 30 kg.
- Human immunodeficiency virus (HIV)-infected (HIV1/2 antibody-positive) patients may
participate if they meet all the following eligibility requirements:
- They must be on an anti-retroviral regimen with evidence of at least two
undetectable viral loads within the past 6 months on this same regimen; the most
recent undetectable viral load must be within the past 12 weeks.
- They must have a CD4 count >= 250 cells/uL over the past 6 months on this same
anti-retroviral regimen and must not have had a CD4 count < 200 cells/uL over the
past 2 years, unless it was deemed related to chemotherapy-induced bone marrow
suppression.
- For patients who have received chemotherapy in the past 6 months, a CD4
count < 250 cells/uL during chemotherapy is permitted as long as viral loads
were undetectable during this same chemotherapy.
- They must have an undetectable viral load and a CD4 count >= 250 cells/uL within
28 days of enrollment.
- They must not be currently receiving prophylactic therapy for an opportunistic
infection and must not have had an opportunistic infection within the past 6
months.
- Monitoring for HIV-infected patients should include:
- Viral load and CD4 count every 8-10 weeks.
- The effects of targeted agents on the developing human fetus are unknown. The
cytotoxic agents chosen for combination with MEDI4736 adversely affect human fertility
and gestation. For these reasons, women of childbearing potential and men must agree
to use highly effective contraception prior to study entry for the duration of study
participation and for 6 months following the last dose of a study drug.
- Because there may be a risk for adverse events in nursing infants secondary to
treatment of the mother with these agents, breastfeeding should be discontinued while
the patient is on this trial and for 6 months following the last dose of study drug.
- Patients should be willing not to donate blood while participating in this study or
for at least 90 days following the last dose of study drug.
- Left ventricular ejection fraction greater than 50% or the institutional lower limit
of normal by echocardiography (ECHO) at entry (patients enrolling on Arm 3 only).
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Patients who received prior therapy with a checkpoint inhibitor and were taken off
drug for serious adverse events are excluded. Patients who had prior CTLA-4 inhibitor
treatment and did not experience serious adverse events are eligible for all arms.
Patients who had prior PD-L1/PD-1 inhibitor treatment and did not experience serious
adverse events are excluded from the MEDI4736 (durvalumab) monotherapy arm but are
eligible for the chemotherapy combinations.
- Patients with pancreatic cancer, prostate cancer, or microsatellite stable (MSS)
colorectal cancer, or other histologies where clinical evidence exists that
single-agent inhibition of PD-L1/PD-1 has minimal activity will not receive
single-agent MEDI4736 (durvalumab) but may be eligible to receive this agent with
chemotherapy (Arms 2-7).
- Women who are pregnant or breastfeeding.
- Patients who are receiving any other investigational agents. Patients on other trials
will be eligible as long as they are no longer receiving study treatment.
- 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:
- 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
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (e.g. bronchiolitis obliterans, cryptogenic organizing pneumonia,
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT)
scan. Patients with active tuberculosis (TB) are also excluded.
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of MEDI4736 (durvalumab). The following are exceptions:
- 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 glucocorticoid equivalent dose of another steroid
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- Patients should not be vaccinated with live attenuated vaccines within 30 days before
starting or after completing MEDI4736 (durvalumab) treatment.
- Patients who have a history of seizures will not be eligible, unless they have either
not had seizures or have been on stable doses of anti-seizure medicine and had no
seizures for 4 weeks, in which case they will be eligible. Patients taking
enzyme-inducing anticonvulsants (i.e., carbamazepine, fosphenytoin, oxcarbazepine,
phenobarbital, phenytoin, primidone) will only be eligible for Arm 1 (durvalumab
monotherapy) and Arm 2 (durvalumab + gemcitabine).
- Patients receiving warfarin are not eligible for Arm 4 (capecitabine) due to the
potential for life-threatening interactions. Patients on warfarin are eligible to
enroll in one of the other arms provided there is increased vigilance with respect to
monitoring international normalised ratio (INR)
- Patients with uncontrolled intercurrent illness including, but not limited to
psychiatric illness/social situations that would limit compliance with study
requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or
active (acute or chronic) or uncontrolled severe infection, liver disease such as
cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.,
quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive
hepatitis B surface antigen [HbsAg], quantifiable HCV-ribonucleic acid [RNA]), are not
eligible to participate. Testing for HBV-DNA and HCV-RNA will be mandatory for
patients with hepatocellular carcinoma (HCC) only; testing for hepatitis B or other
infections for eligibility will be performed only if clinically indicated
- History of grade >= 2 infusion reactions or allergic reactions to humanized monoclonal
antibodies.
- History of primary immunodeficiency.
- History of allogeneic organ transplant.
