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QUILT-3.045: NANT Merkel Cell Carcinoma (MCC) Vaccine: Combination Immunotherapy in Subjects With MCC Who Have Progressed on or After PD-L1 Therapy

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ClinicalTrials.gov Identifier: NCT03167164
Recruitment Status : Not yet recruiting
First Posted : May 25, 2017
Last Update Posted : October 30, 2017
Sponsor:
Information provided by (Responsible Party):
NantKwest, Inc.

Brief Summary:
This is a phase 1b/2 study to evaluate the safety and efficacy of metronomic combination therapy in subjects with MCC who have progressed on or after anti-PD-L1 therapy.

Condition or disease Intervention/treatment Phase
Merkel Cell Carcinoma Biological: Avelumab Biological: Bevacizumab Drug: Capecitabine Drug: Cisplatin Drug: Cyclophosphamide Drug: 5-fluorouracil Drug: Leucovorin Drug: nab-Paclitaxel Drug: omega-3-acid ethyl esters Radiation: Stereotactic Body Radiation Therapy Biological: ALT-803 Biological: ETBX-051 Biological: ETBX-061 Biological: GI-6301 Biological: haNK Phase 1 Phase 2

Detailed Description:
Treatment will be administered in two phases. Subjects will continue treatment until they experience progressive disease (PD) or experience unacceptable toxicity (not correctable with dose reduction), withdraw consent, or if the investigator feels it is no longer in the subject's best interest to continue treatment. Those who have a complete response (CR) will enter phase 2 of the study. Subjects may remain on phase 2 of the study for up to 1 year. Treatment will continue in phase 2 until the subject experiences PD or unacceptable toxicity (not correctable with dose reduction), withdraws consent, or if the investigator feels it is no longer in the subject's best interest to continue treatment.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 67 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: NANT Merkel Cell Carcinoma (MCC) Vaccine: Combination Immunotherapy in Subjects With MCC Who Have Progressed on or After Anti-programmed Death-ligand 1 (PD-L1) Therapy
Estimated Study Start Date : December 2017
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Experimental: NANT MCC Vaccine

A combination of agents will be administered to subjects in this study:

avelumab, bevacizumab, capecitabine, cisplatin, cyclophosphamide, 5-fluorouracil, leucovorin, nab-paclitaxel, omega-3-acid ethyl esters, stereotactic body radiation therapy, ALT-803, ETBX-051, ETBX-061, GI-6301, and haNK.

Biological: Avelumab
Fully human anti-PD-L1 IgG1 lambda monoclonal antibody

Biological: Bevacizumab
Recombinant human anti-VEGF IgG1 monoclonal antibody

Drug: Capecitabine
5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine

Drug: Cisplatin
(SP-4-2)-diamminedichloroplatinum(II)

Drug: Cyclophosphamide
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate

Drug: 5-fluorouracil
5-fluoro-2,4 (1H,3H)-pyrimidinedione

Drug: Leucovorin
Calcium N-[p-[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1)

Drug: nab-Paclitaxel
5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine

Drug: omega-3-acid ethyl esters
Omega-3-acid ethyl esters

Radiation: Stereotactic Body Radiation Therapy
radiation

Biological: ALT-803
Recombinant human super agonist interleukin-15 (IL-15) complex

Biological: ETBX-051
Ad5 [E1-, E2b-]-Brachyury

Biological: ETBX-061
Ad5 [E1-, E2b-]-MUC1

Biological: GI-6301
Heat-killed S. cerevisiae yeast expressing the human Brachyury (hBrachyury) oncoprotein

Biological: haNK
NK-92 [CD16.158V, ER IL-2] (high-affinity activated Natural Killer cells)




Primary Outcome Measures :
  1. Incidence of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), graded using the NCI CTCAE Version 4.03. [ Time Frame: 1 year ]
    Phase 1b primary endpoint

  2. Objective response rate by RECIST Version 1.1 [ Time Frame: 1 year ]
    Phase 2 primary endpoint

  3. Objective response rate by irRC [ Time Frame: 1 year ]
    Phase 2 primary endpoint


Secondary Outcome Measures :
  1. Objective response rate by RECIST Version 1.1 [ Time Frame: 1 year ]
    Phase 1b secondary endpoint

  2. Objective response rate by irRC [ Time Frame: 1 year ]
    Phase 1b secondary endpoint

  3. Progression-free survival by RECIST Version 1.1 [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  4. Progression-free survival by irRC [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  5. Overall survival [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  6. Duration of response [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  7. Disease control rate (confirmed complete response, partial response, or stable disease lasting for at least 2 months) [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  8. Quality of life by patient-reported outcome using Functional Assessment of Cancer Therapy-Melanoma (FACT-M) Questionnaire [ Time Frame: 2 years ]
    Phase 1b and Phase 2 secondary endpoint

  9. Incidence of treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), graded using the NCI CTCAE Version 4.03 [ Time Frame: 1 year ]
    Phase 2 secondary endpoint



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Able to understand and provide a signed informed consent that fulfills the relevant IRB or IEC guidelines.
  3. Histologically-confirmed metastatic or unresectable MCC with progression on or after anti-PD-L1 therapy (eg, avelumab).
  4. ECOG performance status of 0 to 2.
  5. Have at least 1 measurable lesion of ≥ 1.5 cm.
  6. Must have a recent tumor biopsy specimen obtained following the conclusion of the most recent anti-cancer treatment. If a historic specimen is not available, the subject must be willing to undergo a biopsy during the screening period.
  7. Must be willing to provide blood samples for exploratory analyses, and if considered safe by the investigator, a tumor biopsy specimen at 8 weeks after the start of treatment.
  8. Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
  9. Agreement to practice effective contraception for female subjects of child-bearing potential and non-sterile males. Female subjects of child-bearing potential must agree to use effective contraception for up to 1 year after completion of therapy, and non-sterile male subjects must agree to use a condom for up to 4 months after treatment.

Exclusion Criteria:

  1. History of persistent grade 2 or higher (CTCAE Version 4.03) hematologic toxicity resulting from previous therapy.
  2. History of other active malignancies or brain metastasis except: controlled basal cell carcinoma; prior history of in situ cancer (eg, breast, melanoma, cervical); prior history of prostate cancer that is not under active systemic treatment (except hormonal therapy) and with undetectable PSA (< 0.2 ng/mL); bulky (≥ 1.5 cm) disease with metastasis in the central hilar area of the chest and involving the pulmonary vasculature. Subjects with a history of another malignancy must have > 5 years without evidence of disease.
  3. Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment-related complications.
  4. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma).
  5. History of organ transplant requiring immunosuppression.
  6. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
  7. Requires whole blood transfusion to meet eligibility criteria.
  8. Inadequate organ function, evidenced by the following laboratory results:

    1. WBC count < 3,500 cells/mm3.
    2. Absolute neutrophil count < 1,500 cells/mm3.
    3. Platelet count < 100,000 cells/mm3.
    4. Hemoglobin < 9 g/dL.
    5. Total bilirubin greater than the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome).
    6. AST (SGOT)) or ALT (SGPT) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases).
    7. Alkaline phosphatase levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or >10 × ULN in subjects with bone metastases).
    8. Serum creatinine > 2.0 mg/dL or 177 μmol/L.
    9. INR or aPTT or PTT >1.5 × ULN (unless on therapeutic anti-coagulation).
  9. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication.
  10. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy.
  11. Positive results of screening test for HIV, HBV, or HCV.
  12. Current chronic daily treatment (continuous for > 3 months) with systemic corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed.
  13. Known hypersensitivity to any component of the study medication(s).
  14. Subjects taking any medication(s) (herbal or prescribed) known to have an adverse drug reaction with any of the study medications.
  15. Concurrent or prior use of a strong CYP3A4 inhibitor (including ketoconazole, itraconazole, posaconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, and grapefruit products) or strong CYP3A4 inducers (including phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St John's Wort) within 14 days before study day 1.
  16. Concurrent or prior use of a strong CYP2C8 inhibitor (gemfibrozil) or moderate CYP2C8 inducer (rifampin) within 14 days before study day 1.
  17. Participation in an investigational drug study or history of receiving any investigational treatment within 14 days prior to screening for this study, except for testosterone-lowering therapy in men with prostate cancer.
  18. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.
  19. Concurrent participation in any interventional clinical trial.
  20. Pregnant and nursing women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03167164


Contacts
Contact: Jim Farmer (310) 853-7522 Jim.Farmer@NantKwest.com

Sponsors and Collaborators
NantKwest, Inc.

Responsible Party: NantKwest, Inc.
ClinicalTrials.gov Identifier: NCT03167164     History of Changes
Other Study ID Numbers: QUILT-3.045
First Posted: May 25, 2017    Key Record Dates
Last Update Posted: October 30, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Merkel Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Vaccines
Cyclophosphamide
Fluorouracil
Paclitaxel
Cisplatin
Bevacizumab
Capecitabine
Albumin-Bound Paclitaxel
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators