Details

Details

Title A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS 9973 in Subjects with Relapsed or Refractory Hematologic Malignancies

IRB GSI1Z13

CC 14-074

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Chronic Lymphocytic (CLL), Lymphoma, Other iNHL

Drug GS9973

Description

Description

Primary Objective
  • To evaluate the efficacy of GS-9973 in subjects with relapsed or refractory hematologic malignancies
Secondary Objectives
  • To evaluate the safety and tolerability of GS-9973 in subjects with relapsed or refractory hematologic malignancies
  • To evaluate GS-9973 exposures in subjects with relapsed or refractory hematologic Malignancies
Inclusion Criteria

Inclusion Criteria

  1. Male or female ≥ 18 years of age.
    • Diagnosis of B-cell iNHL, DLBCL, MCL (mantle cell, nodal, diffuse or blastoid), or CLL as documented by medical records and with histology based on criteria established by the World Health Organization. If the subject has DLBCL, subtyping is required. Submission of 15 unstained slides is required for subtyping if the subtype is not already known. Subjects for whom tissue is not available but the subtype is already known may be included if pathology report including the subtype is provided.
    • If the subject has iNHL, the lymph node histology report confirms 1 of the following subtypes:
      • FL Grade 1, 2, or 3a
      • SLL (ie., SLL/CLL histology with an absolute lymphocyte count of < 5 x 109/L at diagnosis and on Screening laboratory assessment performed within 35 days prior to the start of study drug administration)
      • LPL/WM
      • MZL (splenic, nodal, or extranodal)
  2. For institutions that have Phase 3 or Phase 4 protocols studying idelalisib Zydelig: subjects with malignancies being studied in these protocols must be a screen failure in the respective idelalisib protocol.
  3. Prior treatment for lymphoid malignancy and requiring treatment for progressive disease. Criteria for progressive disease is established Cheson criteria for NHL and by IWCLL criteria for CLL
    • LPL/WM patients do not need to have progressive disease but need to meet criteria of needing treatment per Update on Recommendations for Assessing Response from the Third International Workshop onWaldenstrom's Macroglobulinemia
  4. (see Section 4 for details):
    • Subjects with denovo DLBCL for whom there is no curative option with conventional treatment
    • If the subject has MCL, iNHL, or BCR based therapy naive CLL, the prior treatment must be comprised of at least 1 of the following:
      • regimen containing a therapeutic antibody administered for ≥ 2 doses of antibody treatment
      • regimen containing ≥ 1 cytotoxic agent administered for ≥ 2 cycles of cytotoxic treatment
      • regimen containing yttrium90-ibritumomab tiuxetan or iodine131-tositumomab
      • experimental therapy as part of clinical trial protocol
    • The previously BCR treated patients will be limited to subjects with CLL (other BCR targeted therapies may be accepted after approval of the medical monitor), only in the context of this cohort are Richter's transformation eligible.
      • CLL subjects whom have had more than 1 BCR targeted therapy will be enrolled into the cohort of the most recent treatment ibrutinib or idelalisib received prior to progression.
  5. Presence of radiographically measurable progressive disease as defined using Cheson criteria for NHL, and iNHL and by IWCLL criteria for CLL; lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥ 1 lesion that measures ≥ 2.0 cm in the longest diameter [LD] and ≥ 1.0 cm in the longest perpendicular diameter [LPD] as assessed by CT or MRI);
    • Subjects with LPL/WM who do not have radiographically measurable progressive disease must have a monoclonal serum IgM > 2x ULN as verified by serum protein electrophoresis (SPEP) and with lymphoplasmacytic marrow involvement are eligible. LPL/WM enrollment is limited to those sites which have cryoglobulin analysis capabilities
  6. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [Grade 1, 2, or 3 permitted)
  7. Karnofsky performance status of ≥ 60
  8. Life expectancy of at least 3 months
  9. Required screening laboratory data (within 5 weeks prior to administration of study drug) as shown in Table 4-1. Note: Confirmation should be considered for out-of-range values to determine if the abnormality is real or artifactual. Values used for screening must be obtained within the screening period and should be the most recent measurement obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia with documentation that it is due to malignancy may enroll.
    • ANC ≥ 0.5 x 109/L
    • Platelets ≥ 50 x 109/L
    • Hemoglobin ≥ 80 g/L (8.0 g/dL)
    • Serum total bilirubin ≤ 1.5 x ULN (unless elevated due to Gilbert's syndrome or hemolysis)
    • Serum ALT ≤ 2.5 x ULN
    • Serum AST ≤ 2.5 x ULN
    • Serum creatinine OR Estimated creatinine clearance < 1.5 x ULN OR > 60 ml/min as calculated by the Cockroft-Gault method
    • Coagulation INRa < 1.7
    • Pregnancy β-HCGb Negative
    • HIV Negative HIV antibody
    • HBV Negative HBsAg and negative HBc antibody
    • HCV Negative viral RNA (if HCV antibody is positive)
  10. For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of GS-9973. See Section 7.11 for information regarding recommendations for contraception
  11. For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the start of study drug throughout the study treatment period and for 90 days following the last dose of GS-9973 or GS-9973 SDD and to refrain from sperm donation from the start of study drug throughout the study treatment period and for 90 days following the last dose of GS-9973 or GS-9973 SDD. See Section 7.11 for information regarding recommendations for contraception.
  12. Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions
  13. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of any study specific procedures.
Exclusion Criteria

Exclusion Criteria

  1. Known histological transformation from iNHL or CLL to an aggressive form of NHL (ie, Richter transformation) if the CLL patient has not had ibrutinib or idelalisib as their immediately prior therapy. CLL patients who were treated with a BCR inhibitor as the most recent therapy and who experience a transformation of their tumor, will not be excluded. Subjects who have a history of iNHL or CLL with a subsequent confirmation high grade histology will be considered transformed for purpose of this study. Note: Biopsy documentation of the absence or presence of transformation is not required
  2. Known active central nervous system or leptomeningeal lymphoma. Note: Central nervous system imaging is only required in subjects with suspected lymphomatous involvement based on symptoms or signs
  3. Presence of known intermediate- or high-grade myelodysplastic syndrome (ie, subjects are excluded who have ≥ 5 bone marrow blasts; karotypic abnormalities other than normal, Y deletion, 5q deletion, or 20q deletion; or ≥ 2 lineages of cytopenias)
  4. Because they are likely to interfere with GS-9973 absorption, current therapy with agents that reduce gastric acidity, including but not limited to antacids, H2 inhibitors, and proton pump inhibitors
  5. History of any prior lymphoid malignancy other than registrational histology except for CLL subjects with prior BCR therapy
    • Subjects with diagnoses other than CLL who were previously treated with a BCR inhibitor are excluded from this study.
  6. History of non-lymphoid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to start of study therapy, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years
  7. Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study drug. Note: Subjects with localized fungal infections of skin or nails are eligible.
  8. Ongoing, drug-induced liver injury, chronic active Hepatitis C Virus (HCV), chronic active Hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
  9. Ongoing (within the past 6 weeks) hepatic encephalopathy
  10. Ongoing drug-induced pneumonitis
  11. Ongoing inflammatory bowel disease
  12. Ongoing alcohol or drug addiction as determined by investigator
  13. Pregnancy or breastfeeding
  14. History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
  15. Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid malignancy. Concurrent use of methotrexate for rheumatologic conditions is permitted. Note: Subjects may use topical, enteric, or inhaled corticosteroids as therapy for comorbid conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤ 5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted. During study participation, subjects may receive systemic or other corticosteroids needed for treatment-emergent comorbid conditions. See next entry for exception related to steroids.
  16. Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 21 days prior to study drug. Exception: the cohorts with relapsed CLL following BCR pathway inhibitors whom in the opinion of the investigators cannot have a 21 day washout period ≥5 half lives washout period will be allowed, along with up to 20 mg of prednisone at the start of the trial, for control of disease related symptoms, with planned taper over 2 weeks
  17. Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the subject or impair the assessment of study results