An Early Phase Study with the Drug LOXO-305 in Patients with PreviouslyTreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma(CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

Phase 1

• Conditions: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Non-Hodgkin Lymphoma (NHL); MedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10003908Term: B-cell small lymphocytic lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 22.0Level: PTClassification code 10029547Term: Non-Hodgkin's lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-003340-24-GB
• Lead Sponsor: oxo Oncology, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-12-19
• Last Update Posted: 26 October 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 850

Inclusion Criteria

Phase 1/2 LOXO-305 monotherapy: Ph1 dose escalation and expansion
1.Histologically confirmed B-cell malignancy (eg CLL/ SLL, WM, NHL) Failed and intolerant to either = 2 prior standard of care regimens given in combination or sequentially OR have received 1 prior BTK-containing regimen when a BTK inhibitor is approved as first line therapy
2.Adequate hematologic status, defined as the following on or within 7 days of C1D1 before treatment;see also Exclusion Criterion 8. Please refer to Protocol to complete list.

Phase2:
Sponsor will provide cohort assignment for patient based on diagnosis and prior treatment history information provided during eligibility assessment.Specified cohorts and pretreatment requirements are:
Ch1 MCL:Diagnosis of non-blastoid MCL with documentation of either overexpression of cyclin D1 and/or t(11;14) and treated with a prior BTK inhibitor-containing regimen
Ch2 CLL/SLL:Diagnosis of CLL/SLL by IWCLL 2018 criteria and treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen
Ch3 CLL/SLL:Diagnosis of CLL/SLL by IWCLL 2018 and not previously treated. Patients in UK will not be screened or enrolled to this cohort.
Ch4 CLL/SLL: Diagnosis of CLL/SLL by IWCLL 2018 and previously treated, BTK inhibitor naive
Ch5 WM:Diagnosis of WM with documentation of MYD88 mutation who have received prior therapy with a BTK inhibitor-containing regimen Ch6 MZL:Diagnosis of MZL who have received a prior BTK inhibitor-containing regimen
Cohort 6 MZL: Confirmed diagnosis of MZL who have received a prior BTK inhibitor-containing regimen
Ch7 Defined as CLL/SLL or NHL not otherwise specified in Cohorts 1 through 6, inclusive of CLL/SLL, Richter's transformation or low-grade NHL with transformation, blastoid MCL and patients with history of CNS involvement or primary CNS lymphoma.In the event the Sponsor electively closes Ch2-4 prior to completion, patients with CLL/SLL who are ineligible to participate in or unable to access late Phase studies of LOXO-305 would remain eligible to enroll in this cohort. In the UK, Cohort 7 may enroll patients who have received prior therapy, who were intolerant of or refused standard first line therapy or patients for whom no approved therapy with demonstrated clinical benefit is available.

All patients must have disease requiring treatment.
All Patients:
1.Eastern Cooperative Oncology Group (ECOG) 0-2
2.At least 18 years of age
3.Confirmation of availability of tumor sample obtained after most recent treatment
4.Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin time (PT) or international normalized ratio (INR) not greater than 1.5 × ULN
5.Adequate hepatic function defined as:
a.ALT or AST = 2.5 × ULN or = 5 × ULN with documented liver metastases
b.Total bilirubin = 1.5 × ULN or = 3 × ULN with documented liver metastases.If total bilirubin is > 1.5 x ULN then direct/indirect or conjugated/unconjugated bilirubin tests should be performed and meet the parameter specified. For patients with hemolysis and/or Gilbert's syndrome, they may be enrolled if unconjugated/indirect bilirubin is < 5 x ULN and conjugated/direct bilirubin is < 3 x ULN.
6.Adequate renal function defined as creatinine clearance = 30 mL/minute using Cockcroft/Gault Formula:(140 – age) × body weight (kg) × 0.85 (if female) / serum creatinine (mg/dL) × 72
7.Ability to swallow tablets and comply with outpatient treatment, laboratory mon

Exclusion Criteria

All Patients:
1.Investigational agent or anticancer therapy within 5 half-lives prior to planned start of specified study therapy except therapeutic monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of LOXO-305.
a.Continuation of certain standard of care anticancer therapies, including hormonal therapy for breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications
2.Major surgery within 4 weeks prior to planned start of specified study therapy
3.Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving radiation to more than 30% of the bone marrow, or receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment
4.Patients requiring therapeutic anticoagulation with warfarin
5.Any unresolved toxicities from prior therapy greater than CTCAE
(version 5.0) Grade 2 at the time of starting study treatment except for alopecia
6.History of allogeneic or autologous stem cell transplant or chimeric antigen receptor-modified T cell therapy within the 60 days prior to planned start of specified study therapy or with any of the following
a.Active graft versus host disease
b.Cytopenias from incomplete blood cell count recovery post-transplant
c.Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy
d.Ongoing immunosuppressive therapy
7.Known central nervous system involvement by systemic lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible and enrolled to phase 2 Cohort 7 if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval
8.Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts
9.Significant cardiovascular disease defined as:
a.Unstable angina or
b.History of myocardial infarction within 6 months prior to planned start of LOXO-305 or
c.Previously documented left ventricular ejection fraction by any method of = 45% in the 12 months prior to planned start of LOXO-305; assessment of LVEF via echocardiogram or multigated acquisition
(MUGA) scan during Screening should be performed in selected patients as medically indicated or
d.Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification or
e.Uncontrolled or symptomatic arrhythmias
10.Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms and mean QTcF > 470 msec on all 3 ECGs, during Screening
QTcF is calculated using Fridericia's Formula (QTcF): QTcF=QT/(RR0.33) a.Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation
11.Patients who experienced a major bleeding event or grade = 3 arrhythmia on prior treatment with a BTK inhibitor
12.Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (exc

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified