KPT-330 Plus RICE for Relapsed/Refractory Aggressive B-Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study evaluates the addition of selinexor (KPT-330) to RICE chemotherapy in the treatment of relapsed and refractory aggressive B-Cell Lymphoma, with the goal of improved response rates (as compared to RICE chemotherapy alone).

Detailed Description
-----------------
Although aggressive B-cell lymphomas are potentially curable with front-line chemotherapy, at least one-third of patients experience progression or relapse. Second-line regimens such as rituximab, ifosfamide, carboplatin, and etoposide (RICE) are administered with the goal of cytoreduction prior to autologous stem cell transplantation (ASCT) in eligible patients. However, half of patients who receive salvage treatment and ASCT are still not cured. Selinexor is a Selective Inhibitor of Nuclear Export / SINE compound, which is a new class of molecule. SINE compounds have been shown to induce apoptotic cell death in pre-clinical models of AML, CLL, T-ALL, and Ph+ ALL as well as B and T-cell non-Hodgkin lymphomas. Preliminarily, selinexor has demonstrated promising single-agent clinical activity in patients with previously treated NHL including DLBCL, warranting further investigation. Based on promising preclinical and clinical data, selinexor is currently under evaluation in combination with chemotherapy for solid tumors. The investigators hypothesize that the combination of selinexor plus RICE will be well-tolerated and clinically active in participants with previously treated aggressive B-cell lymphomas and propose a phase I trial to evaluate this combination. Moreover, Investigators will evaluate primary patient samples before and after selinexor to investigate the mechanisms of action of selinexor, including the mechanisms by which selinexor sensitizes cells to chemotherapy, and evaluate other novel drug combinations in aggressive B-cell lymphomas.

Official Title
-----------------
A Phase I Investigator-Initiated Study of Selinexor (KPT-330) Plus RICE in Patients With Relapsed or Refractory Aggressive B-cell Lymphomas

Conditions
-----------------
Diffuse Large B-Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: KPT-330
* Drug: Rituximab
* Drug: Etoposide
* Drug: Carboplatin
* Drug: Ifosfamide
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically confirmed aggressive B-cell non-Hodgkin lymphomas: DLBCL including ABC, GCB or PMBCL subtypes Double/triple hit lymphomas Indolent lymphomas transformed to aggressive lymphomas Follicular lymphomas grade 3B Patients must have received at least two cycles of anthracycline based chemotherapy administered with curative intent and one of the following: failed to have achieve at least a partial response after 2 or more cycles failed to achieve a complete response after 6 or more cycles progressed after an initial response Patients must be age ≥18 years. Patients must have at least one site of measurable disease, 1.5 cm in diameter or greater. Patients must have ECOG performance status of 0-2. Patients must have laboratory test results within these ranges: Absolute neutrophil count ≥ 1500/mm³ Platelet count ≥ 100,000/mm³ Serum creatinine clearance ≥40 mL/min Total bilirubin ≤ 1.5x ULN. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis. AST (SGOT) and ALT (SGPT) ≤ 2x ULN Women of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test prior to selinexor treatment. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose. Patients must be able to understand and willing to sign a written informed consent document. Patients must be able to adhere to the study visit schedule and other protocol requirements. Patients must not have any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Patients must not have any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Exclusion Criteria: Patients with hyperuricemia or other potential signs of tumor lysis syndrome Patients with more than minimally symptomatic disease (i.e. > grade 1), high tumor burden, or other indication for urgent treatment. Patients who have had prior malignancies (other than B-cell lymphomas) for ≤5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. Patients who have had other anti-cancer therapy, including radiation or experimental drug or therapy, within 28 days of enrollment. Patients with known HIV, active hepatitis B, active hepatitis C. Patients with known central nervous system involvement by lymphoma.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br>All subjects will receive KPT-330 (selinexor) on days -5 and -3 starting one week before RICE chemotherapy is started. Once chemotherapy starts, selinexor will be given on days 1, 3, and 5 of each chemotherapy cycle. RICE chemotherapy will consist of Rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone. | Drug: KPT-330<br>* KPT-330 administered orally on days -5 and -3 prior to starting chemotherapy. Once chemotherapy starts, KPT-330 will be administered on days 1, 3, and 5 of each cycle. Dose levels will range from 20 mg to 100mg with a standard 3+3 escalation schema.<br>* Other names: Selinexor;Drug: Rituximab<br>* IV Rituximab 375 mg/m2 on D1<br>* Other names: Rituxan;Drug: Etoposide<br>* IV Etoposide 100 mg/m2 on D1-3<br>Drug: Carboplatin<br>* IV Carboplatin AUC 5 on D2<br>Drug: Ifosfamide<br>* IV Ifosfamide 5 g/m2 on D2<br>Drug: Dexamethasone<br>* 20 mg qd on Days -5 and -3. 20 mg qd on Days 1-5<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dosage (MTD) of Selinexor/KPT-330 when combined with RICE chemo in a relapsed/refractory aggressive b-cell lymphoma setting. | The highest dose level at which no more than 1 or 6 patients presents with a dose-limiting toxicity (DLT) during the first 6 cycles of treatment | approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival of subjects treated with KPT-330 + RICE | Overall survival of patients enrolled on KPT-330 + RICE | approximately 24 months per patient | 
| Progression-Free Survival of subjects treated with KPT-330 + RICE | Progression-free survival of patients enrolled on KPT-330+RICE | approximately 24 months per patient | 
| Number of patients who demonstrate a Response to KPT-330+RICE | The efficacy (as assessed by clinical response) of the combination of KPT-330 + RICE in patients with Rel/Ref b-cell lymphoma | approximately 24 months per patient | 
| Number of patients who undergo stem cell collection after induction therapy with KPT-330 + RICE | The number of patients who can feasibly undergo a stem cell transplant after treatment with KPT-330+RICE | approximately 24 months per patient | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DLBCL, Aggressive, Diffuse, Large