NCT02416908

Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Completed Phase 1, PHASE2 Results posted Last updated 13 March 2020

What this trial tests

Phase 1, PHASE2 trial testing Selinexor in Acute Myeloid Leukemia in 40 participants. Completed in 21 June 2019.

Timeline

16 June 2015

Primary endpoint
21 June 2019

21 June 2019

Quick facts

Lead sponsor	Washington University School of Medicine
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	40
Start date	16 June 2015
Primary completion	21 June 2019
Estimated completion	21 June 2019
Sites	1 location across United States

Drugs / interventions tested

• Selinexor — full drug profile →
• Cladribine (CLADRIBINE) — full drug profile →
• G-CSF (g-csf) — full drug profile →
• Cytarabine — full drug profile →
• Bone marrow biopsy

Conditions studied

• Acute Myeloid Leukemia — all drugs for Acute Myeloid Leukemia →

Sponsor

Washington University School of Medicine

Who can join

Adults 18 to 70, any sex, with Acute Myeloid Leukemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

-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

Lymphocyte count decreased

Group	Value	95% CI
Phase I Schedule A and Phase II	32

White blood cell decreased

Group	Value	95% CI
Phase I Schedule A and Phase II	28

Hypophosphatemia

Group	Value	95% CI
Phase I Schedule A and Phase II	26

Platelet count decreased

Group	Value	95% CI
Phase I Schedule A and Phase II	22

Neutrophil count decreased

Group	Value	95% CI
Phase I Schedule A and Phase II	21

Hyponatremia

Group	Value	95% CI
Phase I Schedule A and Phase II	18

Anemia

Group	Value	95% CI
Phase I Schedule A and Phase II	14

Hyperglycemia

Group	Value	95% CI
Phase I Schedule A and Phase II	11

Complete Remission Rate (CR + CRi) Primary · Median follow-up of 34 days

* 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.

Group	Value	95% CI
Phase I Schedule A and Phase II	18

Time to Platelet Engraftment Secondary · 56 days

-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.

Group	Value	95% CI
Phase I Schedule A and Phase II	38	29 – 61

Time to Neutrophil Engraftment Secondary · Up to 2 years

-Time to neutrophil engraftment: Defined as the date of the first dose of study drug to the date that the absolute neutrophil count is \>1,000/mm3

Group	Value	95% CI
Phase I Schedule A and Phase II	28	24 – 58

Event-free Survival Secondary · Up to 2 years (median follow-up of 307 days)

Event-free survival (EFS): Defined as the interval from the date of first dose of study drug to date of treatment failure including progressive disease, recurrence, or discontinuation for any reason (including toxicity, patient preference, initiation of new treatment without documented progression, or death due to any cause).

Group	Value	95% CI
Phase I Schedule A and Phase II	6.1	4.5 – 7.8

Duration of Remission Secondary · Up to 2 years

-Duration of remission (DOR): Defined as the interval from the date complete remission is documented to the date of recurrence.

Group	Value	95% CI
Phase I Schedule A and Phase II	9.1	1.9 – NA

Relapse-free Survival Secondary · Median follow-up of 307 days

Relapse-free survival (RFS): For patients achieving a complete remission, defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause.

Group	Value	95% CI
Phase I Schedule A and Phase II	152	6 – 730

Overall Survival Secondary · Up to 2 years (median follow-up of 307 days)

Overall survival (OS): Defined as the date of first dose of study drug to the date of death from any cause. OS will be evaluated at 3 month intervals for at least 12 months and up to a maximum of 2 years.

Group	Value	95% CI
Phase I Schedule A and Phase II	7.8	5.7 – 14.1

Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation Secondary · Up to 2 years (median follow-up of 307 days)

Allogeneic stem cell transplant utilization: the number of patients proceeding to allogeneic transplant within 2 months following end of study without any additional salvage therapy following study treatment.

Group	Value	95% CI
Phase I Schedule A and Phase II	24

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected from start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever comes first.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase I Schedule A (Selinexor)

Serious: 4/6 (67%)

Deaths: 5/6

Phase I Schedule B (Selinexor)

Serious: 0

Deaths: 0

Phase II (Selinexor)

Serious: 14/34 (41%)

Deaths: 25/34

Selinexor Maintenance Phase (Optional)

Serious: 1/2 (50%)

Deaths: 2/2

Serious adverse events (16 terms)

Reaction	System	Phase I Schedule A (Seline…	Phase I Schedule B (Seline…	Phase II (Selinexor)	Selinexor Maintenance Phas…
Sepsis	Infections and infestations	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—
Constrictive pericarditis	Cardiac disorders	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—
Pancreatitis	Gastrointestinal disorders	—	—	—	—
Fever	General disorders	—	—	—	—
Appendicitis perforated	Infections and infestations	—	—	—	—
Bone infection	Infections and infestations	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—
Soft tissue infection	Infections and infestations	—	—	—	—
Acidosis	Metabolism and nutrition disorders	—	—	—	—
Seizure	Nervous system disorders	—	—	—	—
Pulmonary edema	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—

Other adverse events (168 terms — click to expand)

Reaction	System	Phase I Schedule A (Seline…	Phase I Schedule B (Seline…	Phase II (Selinexor)	Selinexor Maintenance Phas…
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—	—	—
White blood cell decreased	Investigations	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—
Mucositis oral	Gastrointestinal disorders	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—
INR increased	Investigations	—	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—	—
Alkaline phosphatase increased	Investigations	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Proteinuria	Renal and urinary disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—
Weight loss	Investigations	—	—	—	—
Edema limbs	General disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Anemia	Blood and lymphatic system disorders	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—
Hyperkalemia	Metabolism and nutrition disorders	—	—	—	—
Hypermagnesemia	Metabolism and nutrition disorders	—	—	—	—
Hematuria	Renal and urinary disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—	—
Chills	General disorders	—	—	—	—
Skin infection	Infections and infestations	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—
Sinus brachycardia	Cardiac disorders	—	—	—	—
Confusion	Psychiatric disorders	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Pain	General disorders	—	—	—	—
Atelectasis	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—

Most-reported serious reactions: Sepsis, Febrile neutropenia, Constrictive pericarditis, Colitis, Pancreatitis, Fever, Appendicitis perforated, Bone infection.

Data from ClinicalTrials.gov NCT02416908 adverse events section.

Sponsor's own description

Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/refractory AML.

Publications & conference data

6 peer-reviewed publications reference this trial (live from Europe PMC):

1. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells.
   Etchin J, Berezovskaya A, Conway AS, Galinsky IA, et al · · 2017 · cited 99× · PMID 27211268 · DOI 10.1038/leu.2016.145
2. The past, present, and future of CRM1/XPO1 inhibitors.
   Wang AY, Liu H. · · 2019 · cited 85× · PMID 30976603 · DOI 10.21037/sci.2019.02.03
3. Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives.
   Talati C, Sweet KL. · · 2018 · cited 17× · PMID 30405902 · DOI 10.2217/ijh-2018-0001
4. Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities.
   Stahl M, Kim TK, Zeidan AM. · · 2016 · cited 15× · PMID 27822339 · DOI 10.4252/wjsc.v8.i10.316
5. Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?
   Sokolova V, Gruber R, Pammer LM, Kocher F, et al · · 2024 · cited 1× · PMID 39729162 · DOI 10.1007/s11033-024-10169-5
6. Targeting the nuclear export receptor exportin-1 in acute myeloid leukaemia: From biology to clinical translation.
   Liu Y, Yun X, Ding W, Li S, et al · · 2026 · PMID 42071259 · DOI 10.1002/ctm2.70676