Clinical Trials /

Selinexor With Multiple Standard Chemotherapy Regimens in Treating Patients With Advanced Malignancies

NCT02419495

Description:

This phase Ib trial studies the side effects and best dose of selinexor when given together with several different standard chemotherapy regimens in treating patients with malignancies that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Selinexor may stop the growth of cancer cells by blocking enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Studying selinexor with different standard chemotherapy regimens may help doctors learn the side effects and best dose of selinexor that can be given with different types of treatments in one study.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor With Multiple Standard Chemotherapy Regimens in Treating Patients With Advanced Malignancies
  • Official Title: Phase IB Study to Evaluate the Safety of Selinexor (KPT-330) in Combination With Multiple Standard Chemotherapy Agents in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2014-0640
  • SECONDARY ID: NCI-2015-00693
  • SECONDARY ID: 2014-0640
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02419495

Conditions

  • Advanced Malignant Neoplasm
  • Recurrent Malignant Neoplasm
  • Refractory Malignant Neoplasm

Interventions

DrugSynonymsArms
CapecitabineRo 09-1978/000, XelodaArm J (selinexor, capecitabine, oxaliplatin) (ARM CLOSED)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (selinexor, carboplatin) (ARM CLOSED)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm D (selinexor, doxorubicin, cyclophosphamide) (ARM CLOSED)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexArm D (selinexor, doxorubicin, cyclophosphamide) (ARM CLOSED)
Eribulin MesylateB1939 Mesylate, E7389, ER-086526, Halaven, Halichondrin B AnalogArm C (selinexor, eribulin mesylate)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Arm H (selinexor, FOLFIRI) (ARM CLOSED)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440EArm H (selinexor, FOLFIRI) (ARM CLOSED)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinArm H (selinexor, FOLFIRI) (ARM CLOSED)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm M (selinexor, nivolumab
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm K (selinexor, olaparib)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Arm J (selinexor, capecitabine, oxaliplatin) (ARM CLOSED)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm B (selinexor, paclitaxel)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm L (selinexor, pembrolizumab)
Pemetrexed DisodiumAlimta, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium SaltArm F (selinexor, carboplatin, pemetrexed) (ARM CLOSED)
SelinexorCRM1 Nuclear Export Inhibitor KPT-330, KPT-330, Selective Inhibitor of Nuclear Export KPT-330, SINE KPT-330Arm A (selinexor, carboplatin) (ARM CLOSED)
Topotecan HydrochlorideHycamptamine, Hycamtin, SKF S-104864-A, Topotecan HCl, topotecan hydrochloride (oral)Arm G (selinexor, topotecan hydrochloride) (ARM CLOSED)

Purpose

This phase Ib trial studies the side effects and best dose of selinexor when given together with several different standard chemotherapy regimens in treating patients with malignancies that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Selinexor may stop the growth of cancer cells by blocking enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Studying selinexor with different standard chemotherapy regimens may help doctors learn the side effects and best dose of selinexor that can be given with different types of treatments in one study.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the safety and tolerability of selinexor when given in combination with
      standard chemotherapy regimens.

      SECONDARY OBJECTIVES:

      I. To determine disease control and progression free survival of selinexor administered with
      standard chemotherapy treatments.

      EXPLORATORY OBJECTIVES:

      I. To determine the correlation of translational biomarkers. II. To compare serial assessment
      of mutation status in biopsies obtained at baseline and progression after clinical response
      to combination therapy.

      OUTLINE: This is a dose-escalation study of selinexor. Patients are assigned to 1 of 13
      treatment arms.

      ARM A: Patients receive selinexor orally (PO) on days 1, 8, and 15 and carboplatin
      intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in
      the absence of disease progression or unacceptable toxicity. After 6 courses, patients can
      continue single agent selinexor until disease progression. (ARM CLOSED)

      ARM B: Patients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday
      or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) on days 1-14. Patients then
      receive selinexor PO on days 1, 3, 8 and 10 and paclitaxel IV over 3 hours on days 1 and 8.
      Treatment repeats every 21 days in the absence of disease progression or unacceptable
      toxicity. After 8 courses of combination treatment, patients can continue single agent
      selinexor until disease progression.

      ARM C: Patients receive selinexor PO on days 1, 8, and 15 and eribulin mesylate IV over 1
      hour on days 1 and 8. Combination treatment repeats every 21 days for 6 courses in the
      absence of disease progression or unacceptable toxicity. After 6 courses, patients can
      continue single agent selinexor until disease progression.

      ARM D: Patients receive selinexor PO on days 1, 8, and 15, doxorubicin hydrochloride IV over
      90 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days
      for 6 courses in the absence of disease progression or unacceptable toxicity. After 6
      courses, patients can continue single agent selinexor until disease progression. (ARM CLOSED)

      ARM E: Patients receive selinexor PO on days 1, 8, and 15 and carboplatin IV over 30 minutes
      and paclitaxel IV over 3 hours on day 1. Treatment repeats every 21 days for up to 8 courses
      depending on cancer type (6 courses for non-small cell lung cancer, up to 8 courses for
      ovarian cancer and other histological malignancies) in the absence of disease progression or
      unacceptable toxicity. After 6 to 8 courses, patients can continue single agent selinexor
      until disease progression. (ARM CLOSED)

      ARM F: Patients receive selinexor PO on days 1, 8, and 15 and carboplatin IV over 30 minutes
      and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for 6
      courses in the absence of disease progression or unacceptable toxicity. After 6 courses,
      patients can continue single agent selinexor until disease progression. (ARM CLOSED)

      ARM G: Patients receive selinexor PO on days 1, 8, and 15 and topotecan hydrochloride IV over
      30 minutes on days 1-5. Treatment repeats every 21 days for 8 courses in the absence of
      disease progression or unacceptable toxicity. After 8 courses, patients can continue single
      agent selinexor until disease progression. (ARM CLOSED)

      ARM H: Patients receive selinexor PO on days 1, 8, 15 and 22, irinotecan hydrochloride IV
      over 90 minutes, fluorouracil continuous IV and leucovorin calcium IV over 2 hours on days 1
      and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression
      or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until
      disease progression. (ARM CLOSED)

      ARM I: Patients receive selinexor PO on days 1, 8 and 15 and irinotecan hydrochloride IV over
      90 minutes on days 1 and 8. Treatment repeats every 21 days for up to 8 courses in the
      absence of disease progression or unacceptable toxicity. After 8 courses, patients can
      continue single agent selinexor until disease progression. (ARM CLOSED)

      ARM J: Patients receive selinexor PO on days 1, 8 and 15, capecitabine PO twice daily (BID)
      on days 1-14 and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 21 days for up
      to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses,
      patients can continue single agent selinexor until disease progression. (ARM CLOSED)

      ARM K: Patients receive selinexor PO on days 1, 8, 15, and 22 and olaparib PO BID on days
      1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      ARM L: Patients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday
      or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) and pembrolizumab IV over 30
      minutes on day 1. Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      ARM M: Patients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday
      or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) and nivolumab IV over 30 minutes
      on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      Patients may continue to receive selinexor and chemotherapy after confirmed progressive
      disease in the absence of clinical deterioration and if the investigator considers that the
      patient continues to receive benefit from the treatment.

      After completion of study treatment, patients are followed up every 12 weeks for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (selinexor, carboplatin) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until disease progression.
  • Carboplatin
  • Selinexor
Arm B (selinexor, paclitaxel)ExperimentalPatients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) on days 1-14. Patients then receive selinexor PO on days 1, 3, 8 and 10 and paclitaxel IV over 3 hours on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. After 8 courses of combination treatment, patients can continue single agent selinexor until disease progression.
  • Paclitaxel
  • Selinexor
Arm C (selinexor, eribulin mesylate)ExperimentalPatients receive selinexor PO on days 1, 8, and 15 and eribulin mesylate IV over 1 hour on days 1 and 8. Combination treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until disease progression.
  • Eribulin Mesylate
  • Selinexor
Arm D (selinexor, doxorubicin, cyclophosphamide) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, and 15, doxorubicin hydrochloride IV over 90 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until disease progression.
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Selinexor
Arm E (selinexor, carboplatin, paclitaxel) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, and 15 and carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1. Treatment repeats every 21 days for up to 8 courses depending con cancer type (6 courses for non-small cell lung cancer, up to 8 courses for ovarian cancer and other histological malignancies) in the absence of disease progression or unacceptable toxicity. After 6 to 8 courses, patients can continue single agent selinexor until disease progression.
  • Carboplatin
  • Paclitaxel
  • Selinexor
Arm F (selinexor, carboplatin, pemetrexed) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, and 15 and carboplatin IV over 30 minutes and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until disease progression.
  • Carboplatin
  • Pemetrexed Disodium
  • Selinexor
Arm G (selinexor, topotecan hydrochloride) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, and 15 and topotecan hydrochloride IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses, patients can continue single agent selinexor until disease progression.
  • Selinexor
  • Topotecan Hydrochloride
Arm H (selinexor, FOLFIRI) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8, 15 and 22, irinotecan hydrochloride IV over 90 minutes, fluorouracil IV continuously over 48 hours and leucovorin calcium IV over 2 hours on days 1 and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients can continue single agent selinexor until disease progression.
  • Fluorouracil
  • Irinotecan Hydrochloride
  • Leucovorin Calcium
  • Selinexor
Arm I (selinexor, irinotecan hydrochloride) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8 and 15 and irinotecan hydrochloride IV over 90 minutes on days 1 and 8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses, patients can continue single agent selinexor until disease progression.
  • Irinotecan Hydrochloride
  • Selinexor
Arm J (selinexor, capecitabine, oxaliplatin) (ARM CLOSED)ExperimentalPatients receive selinexor PO on days 1, 8 and 15, capecitabine PO twice daily (BID) on days 1-14 and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After 8 courses, patients can continue single agent selinexor until disease progression.
  • Capecitabine
  • Oxaliplatin
  • Selinexor
Arm K (selinexor, olaparib)ExperimentalPatients receive selinexor PO on days 1, 8, 15, and 22 and olaparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Selinexor
Arm L (selinexor, pembrolizumab)ExperimentalPatients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Selinexor
Arm M (selinexor, nivolumabExperimentalPatients receive selinexor PO twice weekly (e.g. Monday/Wednesday or Tuesday/Thursday or Wednesday/Friday or Thursday/Saturday or Friday/Sunday) and nivolumab IV over 30 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Selinexor

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed malignant neoplasms (not
             including hematological malignancies and brain tumors) untreated or previously treated
             requiring further treatment; patients must be refractory to, and intolerant of,
             established therapy known to provide clinical benefit for their condition; patients in
             Arm L (pembrolizumab) and Arm M (nivolumab) can be treatment naive and do not have to
             fail first line nivolumab or pembrolizumab if they have disease where pembrolizumab or
             nivolumab are Food and Drug Administration (FDA) approved for the first-line setting

          -  For all arms except Arm L (pembrolizumab) and Arm M (nivolumab), patients must have
             failed prior standard curative chemotherapy for their disease; subjects must have
             failed, be intolerant to, or be ineligible for any potentially curative approved
             treatment, irrespective of line of therapy

          -  Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors
             [RECIST] 1.1)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  The patient must be recovered from a prior major surgery; the major surgery must be
             performed at least 4 weeks prior to consent date

          -  Platelets >= 125 x 10^9/L (for Arm L pembrolizumab and Arm M nivolumab and expansion
             cohorts for all arms, platelets >= 100 x 10^9/L)

          -  Hemoglobin >= 10 g/dL (for Arm L pembrolizumab and Arm M nivolumab and expansion
             cohorts for all arms, hemoglobin >= 9 g/dL

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  White blood cells (WBC) >= 3 x 10^9/L, transfusions and growth factors are allowed

          -  Alanine transaminase (alanine aminotransferase [ALT]) =< 2 x upper normal limit (ULN)
             (in the expansion cohort, patients with known liver involvement may have ALT =< 5 x
             ULN); aspartate aminotransferase (AST) =< 2 x ULN (in the expansion cohort, patients
             with known liver involvement may have AST =< 5 x ULN)

          -  Alkaline phosphatase < 4 x ULN

          -  Total bilirubin =< 2 x ULN (in the expansion cohort, patients with Gilbert's syndrome
             [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of =< 3 x
             ULN)

          -  Albumin >= 3 g/dL

          -  Renal function defined as a calculated or measured glomerular filtration rate (GFR) >=
             30 mL/min

          -  The patient has recovered to grade =< 1 by the National Cancer Institute Common
             Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) from the
             effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other
             targeted therapies, with the exception of alopecia; the exceptions for such effects
             are allowed lab values of =< grade 2 specified elsewhere in these inclusion criteria

          -  Life expectancy of at least 12 weeks

          -  Able to swallow and retain oral medication

          -  Patients must give informed consent according to the rules and regulations of the
             individual participating sites

          -  Negative serum pregnancy test in women of childbearing potential within 7 days of
             first dose of treatment and patients of child-bearing potential must agree to use
             effective contraception during/after 3 months post dose; a woman of childbearing
             potential is defined as a premenopausal female capable of becoming pregnant; this
             includes women on oral, injectable or mechanical contraception; women who are single
             and women whose male sexual partners have been vasectomized or whose male sexual
             partners have received or are utilizing mechanical contraceptive devices

          -  For the Arm B (paclitaxel) expansion cohort, patients must have ovarian carcinoma

          -  For Arm C (eribulin) expansion cohort, patients must have triple negative breast
             cancer (eribulin naive)

          -  For Arm K (olaparib), patients must have pre-identified BRCA mutant cancer

        Exclusion Criteria:

          -  Evidence of complete or partial bowel obstruction

          -  Patients with primary central nervous system (CNS) tumor or CNS tumor involvement;
             however, patients with metastatic CNS tumors may participate in this study if the
             patient is:

               -  > 4 weeks from prior therapy completion (including radiation and/or surgery)

               -  Clinically stable with respect to the CNS tumor at the time of study entry

               -  Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement

               -  Not receiving anti-convulsive medications (that were started for brain
                  metastases)

          -  Need of total parenteral nutrition

          -  Prior treatment with an agent targeting the exportin

          -  Allergic to selinexor or any of the chemotherapy intended to receive

          -  Pregnancy or lactation

          -  Radiation (except planned or ongoing palliative radiation to bone outside of the
             region of measurable disease) =< 3 weeks prior to study drug administration date

          -  Chemotherapy, or immunotherapy or any other systemic anticancer therapy =< 3 weeks
             prior to study drug administration date; patients receiving anti-PD-1 treatment, and
             continue to receiving this treatment in combination with selinexor (Arms L and M), can
             start receiving the selinexor and anti-PD-1 combination without washout of the prior
             anti-PD-1 antibody

          -  Diagnosis or recurrence of invasive cancer other than the present cancer within 3
             years (except basal or squamous cell carcinoma of the skin that has been definitively
             treated)

          -  Major surgery within four weeks before consent date

          -  Unstable cardiovascular function: symptomatic ischemia (chest pain of cardiac origin),
             or uncontrolled clinically significant conduction abnormalities (e.g. ventricular
             tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV] block
             or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB]
             will not be excluded), or congestive heart failure (CHF) of New York Heart Association
             (NYHA) class >= 3, or myocardial infarction (MI) within 3 months of consent date

          -  Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
             antifungals within one week prior to the first dose; active infection with concurrent
             treatment is acceptable only if the patient is clinically stable

          -  Significantly diseased (as determined by the principal investigator [PI] or treating
             physician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea

          -  Treatment with an investigational anti-cancer study drug within 3 weeks prior to study
             drug administration date

          -  Concurrent therapy with approved or investigational anticancer therapeutics

          -  Medical, psychological or social conditions that may interfere with the patient's
             participation in the study or evaluation of the study results

          -  Men whose partner is a woman of child-bearing potential, (i.e. biologically able to
             conceive), and who is not employing two forms of highly effective contraception;
             highly effective contraception (e.g. male condom with spermicide, diaphragm with
             spermicide, intra-uterine device) must be used by both sexes during the study and must
             be continued for 3 months after the end of study treatment; women of child-bearing
             potential is defined as sexually mature women who are not surgically sterile or who
             have not been naturally postmenopausal for at least 12 consecutive months (e.g., who
             has had menses any time in the preceding 12 consecutive months)

          -  For Arms L (pembrolizumab) and M (nivolumab), subjects with an active, known or
             suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism
             only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
             alopecia) not requiring systemic treatment, or conditions not expected to recur in the
             absence of an external trigger are permitted to enroll

          -  For Arms L (pembrolizumab) and M (nivolumab), subjects receiving chronic systemic
             steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or other
             form of immunosuppressive therapy within 7 days before the first dose of study
             treatment; use of inhaled or topical steroids or systemic corticosteroids =< 10 mg is
             permitted

          -  For Arms L (pembrolizumab) and M (nivolumab), history of a prior grade 3 or 4
             immune-related adverse event (irAE) or any grade ocular irAE from prior immunotherapy
      
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 3 years
Safety Issue:
Description:Will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Secondary Outcome Measures

Measure:Disease control rate (complete response, partial response + stable disease for at least 6 months, assessed according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria)
Time Frame:Up to 3 years
Safety Issue:
Description:Estimated separately for each cohort with appropriate 95% confidence intervals.
Measure:Objective tumor response rate (complete response + partial response), assessed according to RECIST 1.1 criteria
Time Frame:Up to 3 years
Safety Issue:
Description:Estimated separately for each cohort with appropriate 95% confidence intervals.
Measure:Progression-free survival (PFS)
Time Frame:The time between the course 1 start date and the date of disease progression or death, whichever is reported first, assessed up to 3 years
Safety Issue:
Description:PFS distribution will be estimated using the Kaplan-Meier product limit method and summary measures such as the median value and probabilities will be reported at selected times (with appropriate 95% confidence intervals).
Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:OS distribution will be estimated using the Kaplan-Meier product limit method and summary measures such as the median value and probabilities will be reported at selected times (with appropriate 95% confidence intervals).
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will be graded according to NCI CTCAE version 4.03.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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