Selinexor in Combination With Thalidomide and Dexamethasone in RRMM

Phase Ib/II Study of ATG-010 in Combination With Thalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma

Multiple myeloma (MM) is an incurable plasma cell cancer that almost all patients eventually relapse despite advancement in treatment strategies. B-cell maturation antigen (BCMA) is a cell surface receptor that expressed primarily by malignant and normal plasma cells. This is a single-arm that includes escalation phase and expansion phase ,Selinexor in Combination withThalidomide and Dexamethasone to Treat Relapsed/Refractory Multiple Myeloma Patients.To evaluate efficacy and safety of Selinexor in combination with Thalidomide and Dexamethasone in RRMM patients received at least one prior lines of therapy

Study Overview

• Status: Not yet recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Thalidomide; Drug: Selinexor; Drug: Dexamethasone

Detailed Description

This is a single-arm and open-label phase Ib/IIa study of Relapsed/Refractory Multiple Myeloma patients who have received at least one prior lines of treatment therapy; Approximately 3-48 patients will be enrolled in the study. In dose escalation phase, patients with RRMM will be treated with thalidomide 100mg/d, dexamethasone 20mg biweekly, and escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively.

Then a phase 2 expansion at the recommended dose level based on phase 1b trial will be conducted to evaluate the efficacy, safety and tolerability.

This arm is 4 weeks per cycle and include a total of 12 cycles.Selinexor RP2D，Thalidomide will be given at 100mg/d d1-28, and Dexamethasone 20 mg/d will be given on day 1, 2,8,9,15,16,22,23. If a patient develops partial intolerance to glucocorticoids (as determined by the Investigator) during the study, a dose reduction of dexamethasone maximum to 10 mg is permitted. If patients do not tolerate this dose, a potential discontinuation or further dose reduction would be allowed.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Li Zheng, M.D., Ph.D; Phone Number: +86-028-85423655; Email: lzheng2005618@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital of Sichuan University
      • Contact: Li Zheng, MD.PhD; Phone Number: +86-028-85423655; Email: lzheng2005618@163.com
      • Principal Investigator: Ting Niu, M.D.,Ph.d
      • Principal Investigator: Li Zheng, M.D.,Ph.d

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:

  1. Known and written informed consent (ICF) voluntarily.
  2. Age ≥ 18 years and ≤ 75 years.
  3. Patients with multiple myeloma who have received first-line treatment (induction, autologous transplantation and maintenance as the same first-line treatment) and achieved at least partial remission in induction.
  4. At or after accepting first-line regimen, subjects must have progression disease (PD) recorded which is determined by researcher according to IMWG criteria.
  5. Any clinically significant non-hematological toxicities (except for hair loss, peripheral neuropathy, which is otherwise stipulated in Article 13 of the exclusion criteria) that relevant to previous therapies must have resolved to ≤Grade 2 prior to first dose of study drug.
  6. Adequate hepatic function: total bilirubin < 2× upper limit of normal (ULN) (for patients with Gilbert's syndrome, a total bilirubin of < 3× ULN is required), AST < 2.5× ULN, and ALT < 2.5× ULN.
  7. Adequate renal function: estimated creatinine clearance ≥ 20 mL/min (calculated using the formula of Cockroft-Gault).
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

  9. Measurable MM as defined by at least one of the following:

     1. Serum M-protein (SPEP) ≥ 10 g/L
     2. 24 hours-Urinary M-protein excretion ≥ 0.2 g (200 mg)
     3. Serum FLC ≥ 100 mg/L with abnormal FLC ratio
  10. Expected survival is more than 6 months.

  11. Adequate hematopoietic function (no blood transfusion within 2 weeks and no G-CSF/GM-CSF supportive treatment within 1 week prior to screening test):

      1. Hemoglobin level ≥ 80 g/L
      2. ANC ≥ 1,000/mm3 (1.0×109/L)
      3. Platelet count ≥ 75,000/mm3 (75×109/L)

  12. Female patients of childbearing potential must meet below two criteria:

      1. must agree to use effective contraception methods since signature in ICF, throughout the study and for 3 months following the last dose of study treatment.
      2. must have a negative serum pregnancy test at screening. Note: A woman is considered of childbearing potential following menarche and until becoming postmenopausal (defined as no menstrual period for a minimum of 12 months) or permanently sterile (having undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy). A woman who is taking oral contraceptive or using intrauterine device is considered of childbearing potential.
  13. Male patients (including those who have received vasectomy) must use a condom if sexually active with a female of child-bearing potential throughout the study and for 3 months following the last dose of study treatment.

Exclusion Criteria:

• Patients who meet any of the following criteria will not be enrolled:

  1. Asymptomatic (smoldering) MM.
  2. Plasma cell leukemia.
  3. Documented active amyloidosis.
  4. Previously refractory or intolerant to immunomodulators.
  5. Pregnancy or breastfeeding.
  6. Major surgery was performed within 4 weeks prior to the first study.

  7. Patients with active, unstable cardiovascular diseases, fits any of the following:

     1. Symptomatic ischemia, or
     2. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with first-degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) are allowed), or
     3. Congestive heart failure (CHF) of New York Heart Association (NYHA) ≥ Grade 3, or
     4. Acute myocardial infarction (AMI) within 3 months prior to the first dose of study drug.
  8. Uncontrolled active infection within 1 week prior to the first dose of study drug.
  9. Known HIV positive.

  10. Known active hepatitis A, B, or C infection; or known positive for HCV RNA or HBsAg.

      (Note: patients with HBsAg negative but HBc Ab positive need further HBV-DNA test, excluded if HBV-DNA ≥103 , if HBV-DNA <103 need anti-viral drugs)

  11. Prior malignancy that required treatment or has shown evidence of recurrence (except for skin basal-cell carcinoma and in-situ carcinoma including squamous cell carcinoma, bladder cancer in situ, endometrial cancer in situ, cervical cancer in situ/atypical hyperplasia, prostate cancer incidental finding (T1a or T1b), or breast cancer in situ) within 5 years prior to the first dose of study drug.
  12. Active GI dysfunction interfering with the ability to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment.
  13. Grade ≥ 3 peripheral neuropathy, and Grade ≥ 2 painful neuropathy, within 3 weeks prior to the first dose of study drug.
  14. Previous history of deep vein thrombosis.
  15. Serious, active psychiatric, or medical conditions which, in the opinion of the Investigator, could interfere with study treatment.
  16. Participation in an investigational anti-cancer clinical study within 3 weeks or 5 half-lives (T1/2) prior to the first dose of study drug.
  17. Received ASCT within 12 weeks prior to the first dose of study drug or previous allogeneic stem cell transplantation (no time limitation).
  18. Treatment with an approved or trial anticancer drug was given within 4 weeks prior to the first study.
  19. Known intolerance to or contraindication for glucocorticoid therapy.
  20. Prior exposure to a SINE compound.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Selinexor in combination with thalidomide and Dexamethasone; Selinexor in combination with thalidomide and Dexamethasone. Thalidomide will be given at 100mg/d d1-28,and Dexamethasone 20 mg/d will be given on day 1, 2,8,9,15,16,22,23. Treatment will be administered in 28-day cycles,include a total of 12 cycles. Selinexor dose escalation: 60, 80, 100mg respectively on day 1,8,15,22 for 4-week cycles. Then Selinexor will be given at the recommended dose level on phase II.

Drug: Thalidomide; 100mg/d, Po. on day1-28; Other Names: fǎn yìng tíng; Drug: Selinexor; Selinexor (ATG-010# is a first-in-class, oral selective exportin 1 (XPO1) inhibitor (1,2). Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus along with inhibition of translation of oncoprotein mRNAs.; Other Names: ATG-010; Drug: Dexamethasone; 20 mg/d Po. on day 1, 2,8,9,15,16,22,23; Other Names: Dex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR in each arm: partial response (PR) + very good partial response (VGPR) + complete response (CR)	Assessed from the date of first dose of study treatment until the date that PD assessed up to 12months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Duration from start of study treatment to PD or death (regardless of cause), whichever comes first	12 months
Clinical Benefit Rate (CBR)	Clinical Benefit Rate (CBR=ORR+Minor Response [MR])	12 months
Disease Control Rate (DCR)	Disease Control Rate (DCR=CBR+Stable Disease[SD; for a minimum of 12 weeks])	12 months
Number of Participants with Adverse Events	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	From first dose of study drug administration to end of treatment (up to 12 months)
Overall Survival (OS)	The estimates of Kaplan-Meier	12 months
Minimal Residual Disease (MRD)	To evaluate the minimal residual disease in CR and sCR patients	12 months
Duration of Response (DOR)	Duration from the first observation of at least PR to time of disease progression, or deaths due to disease progression, whichever occurs first.	12 months

Collaborators and Investigators

• Sponsor: Li Zheng
• Investigators: Principal Investigator: Ting Niu, M.D., Ph.D, West China Hospital; Principal Investigator: Li Zheng, M.D., Ph.D, West China Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): July 6, 2021
• Primary Completion (Anticipated): December 30, 2024
• Study Completion (Anticipated): December 30, 2024

Study Registration Dates

• First Submitted: May 13, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 18, 2021

Study Record Updates

• Last Update Posted (Actual): May 18, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Thalidomide; Multiple Myeloma; Relapsed/Refractory Multiple Myeloma; Selinexor; ATG-010
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Dexamethasone; Thalidomide
• Other Study ID Numbers: ATG-010-IIT-MM-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD results are used for publication,and can be shared with other investigators and sponsors
• IPD Sharing Time Frame: Study Protocol can be shared Starting 12 months after publication
• IPD Sharing Access Criteria: Study Protocol must not be shared with non-participants until after publication and must be authorized by the principal investigator and sponsors
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes