Clinical Trials /

Durvalumab in Combination With Chemotherapy in Treating Patients With Advanced Solid Tumors, (DURVA+ Study)

NCT03907475

Description:

This phase II trial studies the side effects of durvalumab when given together with chemotherapy in treating patients with solid tumors that have spread to others places in the body (advanced). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine hydrochloride, pegylated liposomal doxorubicin hydrochloride, capecitabine, carboplatin, paclitaxel, and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with durvalumab may improve how immune cells respond and attack tumor cells.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Pancreatic Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab in Combination With Chemotherapy in Treating Patients With Advanced Solid Tumors, (DURVA+ Study)
  • Official Title: DURVA+ : Evaluation of the Safety and Pharmacodynamics of Anti-PD-L1 Antibody MEDI4736 (Durvalumab) in Combination With Chemotherapy in Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01886
  • SECONDARY ID: NCI-2019-01886
  • SECONDARY ID: 10292
  • SECONDARY ID: 10292
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT03907475

Conditions

  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Progressive Disease

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaArm IV (capecitabine, durvalumab)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm V (carboplatin, durvalumab)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm I (durvalumab)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineArm II (gemcitabine hydrochloride, durvalumab)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm II (gemcitabine hydrochloride, durvalumab)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, Protein-bound PaclitaxelArm VII (nab-paclitaxel, durvalumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm VI (paclitaxel, durvalumab)
Pegylated Liposomal Doxorubicin HydrochlorideATI-0918, Caelyx, DOX-SL, Doxil, Doxilen, Doxorubicin HCl Liposomal, Doxorubicin HCl Liposome, doxorubicin hydrochloride liposome, Duomeisu, Evacet, LipoDox, Lipodox 50, Liposomal Adriamycin, liposomal doxorubicin hydrochloride, Liposomal-Encapsulated Doxorubicin, Pegylated Doxorubicin HCl Liposome, S-Liposomal Doxorubicin, Stealth Liposomal Doxorubicin, TLC D-99Arm III (pegylated liposomal doxorubicin, durvalumab)

Purpose

This phase II trial studies the side effects of durvalumab when given together with chemotherapy in treating patients with solid tumors that have spread to others places in the body. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as gemcitabine, liposomal doxorubicin, capecitabine, carboplatin, paclitaxel, and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with durvalumab may improve how immune cells respond and attack tumor cells.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (durvalumab)Active ComparatorPatients receive durvalumab 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.
  • Durvalumab
Arm II (gemcitabine hydrochloride, durvalumab)ExperimentalPatients 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.
  • Durvalumab
  • Gemcitabine
  • Gemcitabine Hydrochloride
Arm III (pegylated liposomal doxorubicin, durvalumab)ExperimentalPatients 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.
  • Durvalumab
  • Pegylated Liposomal Doxorubicin Hydrochloride
Arm IV (capecitabine, durvalumab)ExperimentalPatients receive capecitabine PO 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.
  • Capecitabine
  • Durvalumab
Arm V (carboplatin, durvalumab)ExperimentalPatients 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.
  • Carboplatin
  • Durvalumab
Arm VI (paclitaxel, durvalumab)ExperimentalPatients 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.
  • Durvalumab
  • Paclitaxel
Arm VII (nab-paclitaxel, durvalumab)ExperimentalPatients 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.
  • Durvalumab
  • Nab-paclitaxel

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 4 cycles
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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