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

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ClinicalTrials.gov Identifier: NCT03907475
Recruitment Status : Not yet recruiting
First Posted : April 9, 2019
Last Update Posted : April 30, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 3, 2019
First Posted Date  ICMJE April 9, 2019
Last Update Posted Date April 30, 2019
Estimated Study Start Date  ICMJE November 14, 2019
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
Incidence of adverse events [ Time Frame: Up to 4 cycles ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03907475 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: April 29, 2019)
  • Changes in the immune microenvironment [ Time Frame: Baseline up to 3 months after the last dose of study drug ]
    Will assess how these changes alter the pharmacodynamic effects of a checkpoint inhibitor.
  • Immunotherapy response of tumor-infiltrating and circulating T cells [ Time Frame: Up to 3 months after the last dose of study drug ]
    Will investigate whether the response to immunotherapy correlates with patients' genetic aberrations and/or the activation status of tumor-infiltrating and circulating T cells.
  • Immune status of the tumor and overall tumor mutational load [ Time Frame: Up to 3 months after the last dose of study drug ]
    Will explore the relationship between immune status of the tumor and overall tumor mutational load.
Original Other Pre-specified Outcome Measures
 (submitted: April 8, 2019)
  • Changes in the immune microenvironment [ Time Frame: Baseline up to 3 months after the last dose of study drug ]
    Will assess how these changes alter the pharmacodynamic effects of a checkpoint inhibitor.
  • Immunotherapy response of tumor-infiltrating and circulating T cells [ Time Frame: Up to 3 months after the last dose of study drug ]
    Will investigate whether the response to immunotherapy correlates with patients' genetic aberrations and/or the activation status of tumor-infiltrating and circulating T cells.
  • Immune status of the tumor [ Time Frame: Up to 3 months after the last dose of study drug ]
    Will explore the relationship between immune status of the tumor and overall tumor mutational load.
 
Descriptive Information
Brief Title  ICMJE Durvalumab in Combination With Chemotherapy in Treating Patients With Advanced Solid Tumors, (DURVA+ Study)
Official Title  ICMJE DURVA+ : Evaluation of the Safety and Pharmacodynamics of Anti-PD-L1 Antibody MEDI4736 (Durvalumab) in Combination With Chemotherapy in Patients With Advanced Solid Tumors
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Progressive Disease
Intervention  ICMJE
  • Drug: Capecitabine
    Given PO
    Other Names:
    • Ro 09-1978/000
    • Xeloda
  • Drug: Carboplatin
    Given IV
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Biological: Durvalumab
    Given IV
    Other Names:
    • Imfinzi
    • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
    • MEDI-4736
    • MEDI4736
  • Drug: Gemcitabine
    Given IV
    Other Names:
    • dFdC
    • dFdCyd
    • Difluorodeoxycytidine
  • Drug: Gemcitabine Hydrochloride
    Given IV
    Other Names:
    • dFdCyd
    • Difluorodeoxycytidine Hydrochloride
    • Gemzar
    • LY-188011
    • LY188011
  • Drug: Nab-paclitaxel
    Given IV
    Other Names:
    • ABI 007
    • ABI-007
    • Abraxane
    • Albumin-bound Paclitaxel
    • Albumin-Stabilized Nanoparticle Paclitaxel
    • Nanoparticle Albumin-bound Paclitaxel
    • Nanoparticle Paclitaxel
    • paclitaxel albumin-stabilized nanoparticle formulation
    • Protein-bound Paclitaxel
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Drug: Pegylated Liposomal Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • ATI-0918
    • Caelyx
    • DOX-SL
    • Doxil
    • Doxilen
    • Doxorubicin HCl Liposome
    • doxorubicin hydrochloride liposome
    • Duomeisu
    • Evacet
    • LipoDox
    • Liposomal Adriamycin
    • liposomal doxorubicin hydrochloride
    • Liposomal-Encapsulated Doxorubicin
    • Pegylated Doxorubicin HCl Liposome
    • S-Liposomal Doxorubicin
    • Stealth Liposomal Doxorubicin
    • TLC D-99
Study Arms  ICMJE
  • Active Comparator: Arm I (durvalumab)
    Patients 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.
    Intervention: Biological: Durvalumab
  • Experimental: Arm II (gemcitabine hydrochloride, durvalumab)
    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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Gemcitabine
    • Drug: Gemcitabine Hydrochloride
  • Experimental: Arm III (pegylated liposomal doxorubicin, durvalumab)
    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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Pegylated Liposomal Doxorubicin Hydrochloride
  • Experimental: Arm IV (capecitabine, durvalumab)
    Patients 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.
    Interventions:
    • Drug: Capecitabine
    • Biological: Durvalumab
  • Experimental: Arm V (carboplatin, durvalumab)
    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.
    Interventions:
    • Drug: Carboplatin
    • Biological: Durvalumab
  • Experimental: Arm VI (paclitaxel, durvalumab)
    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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Paclitaxel
  • Experimental: Arm VII (nab-paclitaxel, durvalumab)
    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.
    Interventions:
    • Biological: Durvalumab
    • Drug: Nab-paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2019)
115
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03907475
Other Study ID Numbers  ICMJE NCI-2019-01886
NCI-2019-01886 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10292 ( Other Identifier: National Cancer Institute LAO )
10292 ( Other Identifier: CTEP )
ZIABC011078 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: A P Chen National Cancer Institute LAO
PRS Account National Cancer Institute (NCI)
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP