PRIMARY OBJECTIVES:
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 22-36,
and durvalumab IV over 60 minutes on days 8, 22, and 36 of cycle 1, days 8 and 22 of cycle 2,
and days 1 and 22 of subsequent cycles. Cycles repeat every 42 days in the absence of disease
progression or unacceptable toxicity.
ARM V: Patients receive carboplatin IV over 30-60 minutes on days 1 and 22 and durvalumab IV
over 60 minutes on days 8, 22, and 36 of cycle 1, days 8 and 22 of cycle 2, and days 1 and 22
of subsequent cycles. Cycles repeat every 42 days in the absence of disease progression or
unacceptable toxicity.
ARM VI: Patients receive paclitaxel IV over 60 minutes on days 1 and 22 and durvalumab IV
over 60 minutes on days 8, 22, and 36 of cycle 1, days 8 and 22 of cycle 2, and days 1 and 22
of subsequent cycles. Cycles repeat every 42 days in the absence of disease progression or
unacceptable toxicity.
ARM VII: Patients receive nab-paclitaxel IV over 30 minutes on days 1 and 22 and durvalumab
IV over 60 minutes on days 8, 22, and 36 of cycle 1, days 8 and 22 of cycle 2, and days 1 and
22 of subsequent cycles. Cycles repeat every 42 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 percutaneous or excisional skin biopsy and be
willing to undergo a tumor biopsy.
- Biopsy samples (frozen tissue harvested per Division of Cancer Treatment and
Diagnosis [DCTD] standard operating procedures [SOP] 340507) 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 evaluable or 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.
- Measured creatinine clearance > 40 mL/min OR calculated creatinine clearance > 40
mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination
of creatinine clearance.
- Any prior therapy, radiotherapy, 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. Radiofrequency ablation (RFA) of localized lesions
should have been performed >= 2 weeks prior to starting treatment.
- 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
8 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 weeks (q8w).
- 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 who had prior treatment with any
of the study chemotherapy agents will not be re-treated with the same chemotherapy,
but may be eligible for the other combination arms.
- Patients with pancreatic cancer, prostate cancer, or microsatellite stable (MSS)
colorectal cancer 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. Use of enzyme-inducing
anticonvulsants during study participation is contraindicated (i.e., carbamazepine,
fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone).
- 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 hepatitis C virus [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.
- Mean QT interval corrected for heart rate (QTc) >= 470 ms using Fridericia's
correction.
- History of grade >= 2 infusion reactions or allergic reactions to humanized monoclonal
antibodies.
- History of primary immunodeficiency.
- History of allogeneic organ transplant.
