A Study of DS-2248 in Participants With Advanced Solid Tumors
Condition: Solid Tumors; Non-small Cell Lung Carcinoma
MeSH terms: Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: DS-2248
Intervention description: Oral capsules, of various strengths (1, 5 , 20 ,or 50 milligrams), once daily during 21-day cycles, until unacceptable treatment-related toxicity or tumor progression are observed.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Heat shock protein 90; Advanced solid tumors; Non-small cell lung carcinoma; Epidermal growth factor receptor; Tyrosine kinase inhibitor acquired resistance; Non-small cell lung carcinoma with acquired resistance to erlotinib, gefitinib, afatinib or others.

Summary:

      This phase 1 clinical trial is intended to understand the safety and tolerability of a new
      anticancer drug in subjects with advanced solid tumors. The patients who qualify for the
      study will receive a once daily dose of the drug taken by mouth and will undergo several
      tests to measure the drug in the blood and to understand the safety, tolerability and any
      effect of the drug on the tumor. The antitumor effect of the drug is not known in human.
    

Eligibility criteria:

        Inclusion Criteria:

          1. A pathologically documented advanced solid malignant tumor refractory to standard
             treatment or for which no standard treatment is available.

          2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

          3. Have adequate bone marrow function, defined as:

               -  Platelet count ≥100x10^9/L or more.

               -  Hemoglobin (Hb) level ≥9.0 g/dL.

               -  Absolute neutrophil count ≥1.5 x 10^9/L.

          4. Have adequate renal function, defined as:

             - Creatinine clearance ≥60 mL/min, as calculated using the modified Cockcroft-Gault
             equation AND creatinine ≤1.5 times upper limit of normal(ULN).

          5. Have adequate hepatic function, defined as:

               -  Aspartate aminotransferase (AST) levels ≤3 times ULN (if liver metastases are
                  present, ≤5x ULN)

               -  Alanine aminotransferase (ALT) levels ≤3x ULN (if liver metastases are present,
                  ≤5x ULN

               -  Bilirubin ≤1.5x ULN

          6. Have adequate blood clotting function, defined as:

             - Prothrombin time and activated partial thromboplastin time ≤1.5x ULN

          7. Participants should be able to provide written informed consent, comply with protocol
             visits and procedures, be able to take oral medication, and not have any active
             infection or chronic co-morbidity that would interfere with therapy.

          8. Participants (male and female) of childbearing/reproductive potential must agree to
             use double-barrier contraceptive measures or avoid intercourse during the study and
             for 90 days after the last dose of study drug. If female and of childbearing
             potential, must have a negative result of a pregnancy test (serum or urine)within 72
             hours prior to initiating study treatment. Surgically sterile individuals and
             postmenopausal females are considered not having child-bearing potential.

          9. Participants must be fully informed about their illness and the investigational nature
             of the study protocol (including foreseeable risks and possible side effects) and must
             sign and date an Institutional Review Board approved informed consent form (including
             Health Insurance Portability and Accountability Act authorization, if applicable)
             before performance of any study-specific procedures or tests.

         10. Participants must be willing to provide pre-existing diagnostic or resected tumor
             samples, such as formalin-fixed paraffin-embedded sections, if available. Providing
             fresh pre-treatment tumor biopsy is optional for participants in dose escalation
             cohorts and in dose expansion Stage 1. Post-treatment biopsies are optional for all
             the participants in the study (dose escalation and dose expansion cohorts).

        Additional Inclusion Criteria for Part 2 (Dose Expansion)

          1. Pathologically documented stage IIIB/IV non-small cell lung cancer.

          2. Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST)
             criteria, Version 1.1.

          3. Participants must meet 1 of the following 3 criteria in order to be included in Part
             2:

               1. Acquired resistance to reversible Epidermal Growth Factor Receptor-Tyrosine
                  Kinase Inhibitor (EGFR-TKI), which should meet the following criteria:

                    -  Previous treatment with single-agent therapy (erlotinib, gefitinib, afatinib
                       or others).

                    -  Either of the following: A tumor that harbors an EGFR mutation known to be
                       associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R,
                       L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by
                       complete response (CR), partial response (PR), or stable disease (SD) ≥6
                       months as defined by RECIST or World Health Organization criteria.

                    -  Systemic progression of disease as defined by RECIST or World Health
                       Organization criteria while treatment with gefitinib, erlotinib, afatinib or
                       others.

                    -  No intervening therapy other than EGFR-TKIs (erlotinib, gefitinib, afatinib
                       or others) after progression on an EGFR-TKI.

                    -  Pre-treatment biopsy (performed via bronchoscopy or imaging guidance) for
                       molecular testing of the tumor is desired but not mandatory for enrollment
                       in Stage 1. However, pre-treatment biopsy within 21 days prior to the first
                       day of treatment is required for enrollment in Stage 2.

               2. Presence of ALK fusion gene in the tumor demonstrated by fluorescence in situ
                  hybridization (FISH) and the participant has acquired resistance to ALK inhibitor
                  therapy.

        Exclusion Criteria:

          1. History of second malignancies or primary central nervous system malignancies, except
             adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or
             other solid tumors curatively treated, with no evidence of disease for ≥3 years.

          2. Gastrointestinal diseases that could affect the absorption of DS-2248.

          3. Subjects with peptic ulcer disease requiring on-going treatment with pH-modifiers

          4. Subjects with history of inflammatory bowel disease.

          5. Subjects with retinal or uveal diseases including macular degeneration with central
             vision loss, retinal detachment, diabetic retinopathy, and uveitis.

          6. Recipient of a stem cell or bone marrow transplant.

          7. Has a concomitant medical condition that would increase the risk of toxicity, in the
             opinion of the Investigator or Sponsor.

          8. Clinically active brain metastases, defined as untreated and symptomatic, or requiring
             therapy with steroids or anticonvulsants to control associated symptoms. Subjects with
             treated brain metastases that are no longer symptomatic and who require no treatment
             with steroids may be included in the study if they have recovered from the acute toxic
             effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of
             whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy).

          9. Has unresolved toxicities from previous anti-cancer therapy, defined as toxicities
             (other than alopecia) not yet resolved to National Cancer Institute (NCI) Common
             Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Grade ≤1 or baseline.
             Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the
             Investigator or Sponsor (e.g., Grade 2 chemotherapy-induced neuropathy).

         10. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy,
             or hormonal therapy (except megestrol acetate as supportive care) within 3 weeks
             before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6
             weeks before study drug treatment; or treatment with small-molecule Tyrosine Kinase
             Inhibitors within 7 days for erlotinib and afatinib and 10 days for gefitinib before
             study drug treatment. Previous and concurrent use of hormone replacement therapy, the
             use of gonadotropin-releasing hormone modulators for prostate cancer, and the use of
             somatostatin analogs for neuroendocrine tumors are permitted.

         11. Therapeutic radiation therapy or major surgery within 4 weeks before study drug
             treatment or palliative radiation therapy within 2 weeks before study drug treatment.

         12. Participation in a clinical drug study within 3 weeks for small-molecule TKIs before
             study drug treatment, or current participation in other investigational procedures.

         13. Concomitant treatment with potent inducers or potent inhibitors of cytochrome P450 3A4
             (CYP3A4).

         14. Concomitant treatment with a medication known to cause renal tubular damage or reduce
             renal perfusion at the dose administered, including aminoglycosides, amphotericin B,
             pentamidine, nonsteroidal anti-inflammatory drugs, and zoledronate.

         15. Corrected QT interval (QTc by Bazett's formula) prolongation at rest, where the mean
             QTc interval is >450 msec based on triplicate ECG.

         16. Pregnant or breastfeeding.

         17. Substance abuse or medical, psychological, or social conditions that may, in the
             opinion of the Investigator, interfere with the subject's participation in the
             clinical study or evaluation of the clinical study results.

         18. Less than 1 week since using systemically acting drugs that increase gastric pH, such
             as H2-blockers and proton pump inhibitors. Antacids should be avoided within 48 hours
             of the first dose of DS-2248.

         19. Use of St. John's Wort (hypericin) is not permitted for 30 days before and during the
             study. Foods or beverages containing grapefruit should be avoided within 48 hours
             before and during the study.

        Additional Exclusion Criteria for Part 2 (Dose Expansion)

          1. Prior treatment with Hsp90 inhibitors

          2. Intervening therapy after progression on an EGFR-TKI (erlotinib, gefitinib, afatinib
             or others), unless re-treated with EGFR-TKI.