study to assess the safety, tolerability and pharmacokinetics of fimepinostat (cudc-907) in patients with lymphoma

Conditions: Lymphoma; Relapsed Lymphoma; Refractory Lymphoma; Relapsed and/or Refractory Lymphoma; Relapsed Ddiffuse Large B-Cell Lymphoma (DLBCL); Refractory Diffuse Large B-Cell Lymphoma (DLBCL); Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma (DLBCL); Double-hit Lymphoma (DHL); Triple-hit Lymphoma (THL); Double-expressor Lymphoma (DEL); High-grade B-cell Lymphoma (HGBL)

Summary: this is a phase 1, open-label, dose-escalation study of fimepinostat (cudc-907) in patients with relapsed and/or refractory diffuse large b-cell lymphoma (dlbcl), or high-grade b-cell lymphoma (hgbl) with or without myc and bcl2 alterations. fimepinostat (cudc-907) is a multi-targeted agent designed to inhibit phosphoinositide 3-kinase (pi3k)and histone deacetylase (hdac). the study is designed to assess the safety, the maximum tolerated dose, the recommended phase 2 dose (rp2d), pharmacokinetics and the anti-cancer activity of oral fimepinostat in combination with 1 or more anti-cancer regimens.


Eligibility criteria:
inclusion criteria: * patients ≥ 18 years of age with any of the following: histopathologically confirmed dlbcl or hgbl (i.e., hgbl with myc, bcl2, and/or bcl6 rearrangements, hgbl, not otherwise specified \[nos\], or dlbcl, nos) that is refractory to, or has relapsed after, treatment with at least 1 prior regimen. eligible sub-types include dhl, thl, or del, as well as dlbcl or hgbl without myc and/or bcl2 alterations. criteria for dhl are concurrent myc translocation+ and bcl2 translocation+ by fluorescence in situ hybridization (fish) (same criteria for thl, which also includes bcl6 translocation+ by fish); criteria for del are concurrent overexpression of myc (≥ 40%) and bcl2 (\> 50%) by immunohistochemistry (ihc). * measurable disease by ct or pet/ct. mri acceptable as per protocol. * eastern cooperative oncology group (ecog) performance status of 0 to 1. * recovery to grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia). * absolute neutrophil count ≥ 1,000/µl; platelets ≥ 75,000/µl for patients with no bone marrow involvement by malignancy; platelets ≥ 50,000/µl for patients with bone marrow involvement by malignancy. * creatinine ≤ 1.5x upper limit of normal (uln); total bilirubin ≤ 1.5x uln; ast/alt ≤ 2.5x uln. * life expectancy of at least 3 months. exclusion criteria: * intention to undergo stem cell transplant (sct) or treatment with chimeric antigen receptor (car) t-cell therapy. * sct therapy within 100 days prior to starting study treatment. * systemic anti-cancer therapy or investigational agent within 3 weeks of study entry, except for nitrosoureas or mitomycin c (6 weeks). * other non-cytotoxic anti-cancer therapy or investigational agent within 5 half-lives or 21 days prior to study treatment, whichever is shorter, as long as any drug related toxicities have resolved to grade 1 or less. dexamethasone up to 12 mg/d is allowed as supportive therapy and does not exclude participation. * contraindication to venetoclax or rituximab. * progressive disease during treatment or within 3 months of stopping prior treatment with a bcl2 inhibitor, histone deacetylase (hdac) inhibitor, or phosphoinositide-3 kinase (pi3k) inhibitor, or prior discontinuation of any of these therapies due to clinically significant toxicity. * graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment. * ongoing treatment with chronic immunosuppressants. * active cns lymphoma. * known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of fimepinostat. * serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment. * uncontrolled or severe cardiovascular disease * unstable or clinically significant concurrent medical condition. * second primary malignancy within 2 years of study entry other than what is specified in the protocol. * known hiv positive, hepatitis b surface antigen-positive status, or known or suspected active hepatitis c infection. * active cmv infection, presence of cmv antigenemia, or evidence of any invasive cmv end organ disease (e.g., cmv colitis).

Keywords: lymphoma dlbcl myc diffuse large b-cell lymphoma hgbl high-grade b-cell lymphoma double-hit lymphoma (dhl) triple-hit lymphoma (thl) double-expressor lymphoma (del) p13k hdac open-label