Study of CLAG + Selinexor in Relapsed or Refractory Acute... | NCT02416908

NCT02416908

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Name	Class
Karyopharm Therapeutics Inc	INDUSTRY

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Phase I Schedule A (selinexor)	Experimental	Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.	Drug: Selinexor Drug: Cladribine Drug: G-CSF Drug: Cytarabine Procedure: Bone marrow biopsy
Phase I Schedule B (selinexor)	Experimental	Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.	Drug: Selinexor Drug: Cladribine Drug: G-CSF Drug: Cytarabine Procedure: Bone marrow biopsy
Phase II (selinexor)	Experimental	Selinexor will be given at the schedule as determined in Phase 1. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

Name	Type	Description	Arm Group Labels	Other Names
Selinexor	Drug		Phase I Schedule A (selinexor) Phase I Schedule B (selinexor) Phase II (selinexor)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants	-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0	From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)
Complete Remission Rate (CR + CRi)	Morphologic complete remission (CR): neutrophil count > 1.0 x 109 /L, platelet count ≥ 100 x 109/L, < 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be <1000/mcl or platelet count <100,000/mcl Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.	Median follow-up of 34 days

Secondary Outcomes

Measure	Description	Time Frame
Time to Platelet Engraftment	-Time to platelet engraftment: Defined as the date of the first dose of study drug to the date that the platelet count is >100,000/mm^3 in the absence of platelet transfusions.	56 days
Time to Neutrophil Engraftment

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed AML (defined using WHO criteria) with one of the following:
- Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or
- First relapse with no prior unsuccessful salvage chemotherapy, or
- Relapsed or refractory to hypomethylating agent, defined as a lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
Age between 18 and 70 years old.
ECOG performance status ≤ 3
Adequate organ function as defined below:
- AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) or Gilbert's disease
- Creatinine clearance >50 ml/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if female.
- Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram
To ensure that no patient will receive a dose of selinexor >70mg/m^2, body surface area (BSA) calculated by Dubois method must be >1.43 m^2
Patients should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important patients understand the need to use birth control while on this study. It is not anticipated that female patients enrolling in this study will be able to conceive. However, in the rare event that this is possible, female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and 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.
Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants).
Previous treatment with CLAG or other chemotherapy regimen containing both cladribine and cytarabine.
Colony stimulating factors within 2 weeks of study.
Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At least 2 months must have elapsed since completion of an allogeneic stem cell transplantation.
Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the exception of hydroxyurea).
Concurrent active malignancy under treatment except prostate or breast cancer undergoing treatment with hormonal therapy.
Treatment with any investigational agent within three weeks prior to first dose in this study.
Active CNS involvement with leukemia.
Unstable cardiovascular function:
- symptomatic ischemia, or
- uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
- congestive heart failure (CHF) of NYHA class ≥3, or
- myocardial infarction (MI) within 3 months
A history of allergic reactions attributed to compounds of similar chemical or biologic composition to KPT-330 or other agents used in the study.
Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable.
Any medical condition which, in the investigator's opinion, could compromise the patient's safety.
Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 5 days of study entry.
Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease significantly affecting gastrointestinal function.
Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
Known human immunodeficiency virus (HIV) infection.
Serious psychiatric or medical conditions that could interfere with treatment.

Name	Affiliation	Role
Geoffrey Uy, M.D.	Washington University School of Medicine	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Washington University School of Medicine		St Louis	Missouri	63110	United States

Label	URL
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine	View source

Arm/Group Information

ID	Title	Description
FG000	Phase I Schedule A (Selinexor)	Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
FG001	Phase I Schedule B (Selinexor)	Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
FG002	Phase II (Selinexor)	Selinexor will be given at the schedule as determined in Phase 1. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.
FG003	Selinexor Maintenance Phase (Optional)	These patients were enrolled and treated in the Phase I Schedule A Arm or the Phase II Arm and if they met the requirements below then they were able to receive maintenance selinexor Available for patients who have achieved a CR or CRi based on post-treatment bone marrow assessment at the time of hematopoietic recovery and are either (1) transplant ineligible or (2) do not have a stem cell transplant donor available 60 mg selinexor on Days 1, 8, 15, and 22 of a 28-day cycle

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Phase I Schedule A (Selinexor)	Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants

-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0

-Phase I Schedule A Arm and Phase II Arm data was combined as all participants received the same dose and schedule of the study regimen.

Posted

Count of Participants

Participants

From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)

ID	Title	Description
OG000	Phase I Schedule A and Phase II	Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Phase I Schedule A (Selinexor)	Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO. Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle). Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8. G-CSF will be given 300 mcg SC once daily on Days 3-8. Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8. Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms

ID	Term
C585161	selinexor
D017338	Cladribine
D016179	Granulocyte Colony-Stimulating Factor
C088327	plerixafor
D003561	Cytarabine

ID	Term
D015762	2-Chloroadenosine
D000241	Adenosine
D011684	Purine Nucleosides
D011687	Purines