Phase II PI3K inhibitor in relapsed, indolent or aggressive NH

Phase 1

Conditions: patients with relapsed, indolent or aggressive Non Hodgkin's lymphomas
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2012-002602-52-ES

Lead Sponsor: Bayer HealthCare AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 60

Inclusion Criteria

All inclusion criteria must be met at the time of screening.
Indolent NHL:
? Histologically confirmed diagnosis of follicular lymphoma (FL), marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).
? Relapsed after >= 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy- and/or immunotherapy-based regimens.
Aggressive NHL:
? Histologically confirmed diagnosis of Grade 3 follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma, or anaplastic large cell lymphoma.
? Relapsed after >= 2 prior chemotherapy regimens, including the following: first-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination chemotherapy regimen. Patients refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL or not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic cells must have received prior rituximab, if available.
Applicable to all patients:
? Ability to understand and willingness to sign written informed consent (IC). Signed informed consent must be obtained before any study specific procedure.
? Male or female patients > 18 years of age.
? Patients with NHL must have at least one measurable lesion according to the recommen-dations of the Report of an International Workshop to Standardize Response Criteria for NHL.
? ECOG performance status <= 2.
? Life expectancy of at least 3 months.
? Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last test drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for patients or their partners is required unless the woman has had a hysterectomy.
? Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
- Total bilirubin <= 1.5 x the upper limit of normal (ULN) (< 3 x ULN for patients with Gilbert-Meulengracht syndrome).
- Alanine transaminase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN (< 5 x ULN for patients with lymphomatous liver involvement of their cancer).
- Amylase and lipase <= 1.5 x the ULN
- Serum creatinine <= 1.5 x the ULN.
- Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m2 according to the modified diet in renal disease (MDRD) abbreviated formula.
- International normalized ratio (INR) or partial thromboplastin time (PTT) < 1.5 x ULN.
Pa

Exclusion Criteria

Patients who meet any of the following criteria at the time of screening will be excluded:
Excluded medical conditions:
? Previous or concurrent cancer that is distinct in primary site or histology from cancer of the lymphatic system within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
? Symptomatic lymphomatous involvement of the brain.
? Congestive heart failure > New York Heart Association (NYHA) class 2.
? Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of test drug.
? Uncontrolled hypertension. (Blood pressure >= 150/90 mmHg despite optimal medical management).
? Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication.
? Non-healing wound, ulcer, or bone fracture.
? Active clinically serious infections (> CTCAE grade 2).
? Known history of human immunodeficiency virus (HIV) infection.
? Known history of chronic hepatitis B or C.
? Patients with seizure disorder requiring medication.
? Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >= CTCAE Grade 3 within 4 weeks of start of study medication.
? Renal failure requiring hemo-or peritoneal dialysis.
? Dehydration of CTCAE grade >= 1 (NCI-CTC version 4.0).
? Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
? Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation.
? History or concurrent condition of interstitial lung disease.
? Persistent proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: creatinine ratio on a random urine sample).
? Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia.
? Current diagnosis of Type 1 or 2 diabetes mellitus, fasting blood glucose > 125 mg/dL (> 6.9 mmol/L) or HbA1c >= 7.0 %
? Patients with phaeochromocytoma.
? Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
? Close affiliation with the investigational site; e.g., a close relative of the investigator, dependent person (e.g. employee or student of the investigational site).
? Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study (see also Section 6.9 and Appendix 14.2).
? Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.

Excluded previous therapies and medications:
? Prior treatment with PI3K inhibitors.
? Treatment with investigational drugs other than PI3K inhibitors within the last 28 days.
? Ongoing immunosuppressive therapy.
? Radiotherapy within 4 weeks prior to treatment start.
? Systemic corticosteroid therapy (ongoing). Patients may be using topical or inhaled corticosteroids.
? History of having r

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The objective of this study is to evaluate the efficacy and safety of BAY 80 6946 in patients with indolent or aggressive Non-Hodgkin's Lymphoma (NHL) who have progressed after standard therapy.;Secondary Objective: Further objectives are to evaluate the pharmacokinetics of BAY 80-6946 and biomarkers.;Primary end point(s): The primary efficacy variable will be the objective tumor response (OR). <br>OR will be assessed in all patients up to 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment.;Timepoint(s) of evaluation of this end point: The primary analysis of the primary efficacy variable will be performed 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment. At that timepoint, an exploratory analysis of all other variables will be performed, if possible.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary efficacy variables in this study will be:<br>? Duration of response (DOR), defined as the time (in days) from first observed tumor response (CR, CRu [applicable only in patients with NHL] or PR) until PD or until death caused by PD.<br>? Progression free survival (PFS), defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression).<br>? Overall survival (OS), defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive.;Timepoint(s) of evaluation of this end point: The final analyses of all secondary efficacy and safety variables and an additional exploratory analysis of the primary efficacy variable will be performed 3 years after the last patient's first treatment or when all patients got PD, whatever comes first.