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VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma)

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ClinicalTrials.gov Identifier: NCT04702425
Recruitment Status : Recruiting
First Posted : January 8, 2021
Last Update Posted : December 19, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

The purpose of the study is to identify doses and schedules of VOB560 and MIK665 that can be safely given and to learn if the combination can have possible benefits for patients with Non-Hodgkin lymphoma (NHL), Multiple Myeloma (MM) or Acute Myeloid Leukemia (AML).

VOB560 and MIK665 are selective and potent blockers respectively of the B-cell lymphoma 2 (BCL2) protein and of the myeloid cell leukaemia 1 (MCL1) protein, proteins that may protect tumor cells from undergoing cell death. VOB560 and MIK665 are designed to block the functions of the BCL2 and MCL1 proteins, so that the tumor cells that rely on these proteins undergo cell death.

Preclinical data suggest that concomitant treatment with VOB560 in combination with MIK665 induces robust anti-tumor activity.


Condition or disease Intervention/treatment Phase
Non-Hodgkin Lymphoma (NHL) Acute Myeloid Leukemia (AML) Multiple Myeloma (MM) Drug: VOB560 Drug: MIK665 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib, Multicenter Study of VOB560 in Combination With MIK665 in Patients With Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma.
Actual Study Start Date : June 23, 2021
Estimated Primary Completion Date : October 17, 2025
Estimated Study Completion Date : October 20, 2025


Arm Intervention/treatment
Experimental: VOB560-MIK665 - Part 1a
Part 1a - Patients with relapsed/refractory non-Hodgkin lymphoma and relapsed/refractory multiple myeloma administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315

Experimental: VOB560-MIK665 - Part 1b
Part 1b - Patients with relapsed/refractory acute myeloid leukemia administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315

Experimental: VOB560-MIK665 - Part 2a
Part 2a - Patients with relapsed/refractory multiple myeloma with at least 10 patients with 1q gain cytogenetic abnormality and 10 patients with high risk R/R MM as defined in (Sonneveld et al 2016) administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315

Experimental: VOB560-MIK665 - Part 2b
Part 2b - Patients with relapsed/refractory non-Hodgkin lymphoma with at least 10 patients with double-hit (DH) lymphoma, based on the overall bad prognosis and limited therapeutic options for patients with DH NHL administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315

Experimental: VOB560-MIK665 - Part 2c
Part 2c - Patients with relapsed/refractory acute myeloid leukemia venetoclax refractory or insensitive with at least 6 patients M5 as proposed by French-American-British (FAB) group, based on the observation that venetoclax resistance in AML M5 can be caused by up-regulation of MCL1 administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315

Experimental: VOB560-MIK665 - Part 2d
Part 2d - Patients with relapsed/refractory acute myeloid leukemia venetoclax naive patients administered VOB560 and MIK665 as an intravenous (IV) infusion.
Drug: VOB560
Powder for concentrate for solution for infusion
Other Name: S65487

Drug: MIK665
Concentrate for solution for infusion
Other Name: S64315




Primary Outcome Measures :
  1. Incidence and severity of AEs and SAEs, including changes in lab values, vital signs, and ECGs [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end

  2. Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment with VOB560 and MIK665 in combination [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end

  3. Frequency of dose interruptions [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end

  4. Frequency of dose reductions [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end

  5. Dose intensities [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end As per European LeukemiaNet (ELN) 2017 for relapse/refractory (R/R) AML As per International Myeloma Working Group (IMWG) 2016 for R/R MM As per Lugano Classification 2014 for R/R NHL

  2. Complete Response (CR) rate (and rate of CR or sCR in R/R MM) [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end As per European LeukemiaNet (ELN) 2017 for relapse/refractory (R/R) AML As per International Myeloma Working Group (IMWG) 2016 for R/R MM As per Lugano Classification 2014 for R/R NHL

  3. Best Overall Response (BOR) [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end As per European LeukemiaNet (ELN) 2017 for relapse/refractory (R/R) AML As per International Myeloma Working Group (IMWG) 2016 for R/R MM As per Lugano Classification 2014 for R/R NHL

  4. Duration Of Response (DOR) [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end Month 18 is assumed to be study end As per European LeukemiaNet (ELN) 2017 for relapse/refractory (R/R) AML As per International Myeloma Working Group (IMWG) 2016 for R/R MM As per Lugano Classification 2014 for R/R NHL

  5. Progression Free Survival (PFS) [ Time Frame: at month 18 ]
    Month 18 is assumed to be study end As per European LeukemiaNet (ELN) 2017 for relapse/refractory (R/R) AML As per International Myeloma Working Group (IMWG) 2016 for R/R MM As per Lugano Classification 2014 for R/R NHL

  6. Area Under Curve (AUC) of VOB560 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  7. Maximum Plasma Concentration (Cmax) ok VOB560 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  8. Terminal elimination half-life (T1/2) of VOB560 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  9. Clearance (CL) of VOB560 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  10. Apparent volume of distribution (Vz) of VOB560 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  11. Area Under Curve (AUC) of MIK665 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  12. Maximum Plasma Concentration (Cmax) ok MIK665 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  13. Terminal elimination half-life (T1/2) of MIK665 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  14. Clearance (CL) of MIK665 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter

  15. Apparent volume of distribution (Vz) of MIK665 [ Time Frame: At the end of Cycle 6 (each cycle is 21 days) ]
    PK parameter



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of one of the following hematologic malignancies:

    • relapsed and/or refractory patients with non-Hodgkin lymphoma with radiographically measurable disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extra nodal lesion at least 1.0 cm in its largest dimension
    • relapsed and/or refractory patients with MM treated with at least 2 prior regimens, including an IMiD, a proteasome inhibitor proteasome inhibitor, and anti-CD38 antibody (if available) and not eligible for treatment with other regimens known to provide clinical benefit, as determined by the investigator.
    • relapsed and/or refractory patients with Acute Myeloid Leukemia (AML), pathologically confirmed diagnosis as defined by the WHO Classification and with ≥ 5% blasts in bone marrow. Following ≥ 1 prior therapies who have relapsed or exhibited refractory disease (primary failure) and are deemed by the investigator not to be candidates for standard therapy, including re-induction with cytarabine or other established therapeutic regimens for patients with AML (patients who are suitable for standard re-induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded).
  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
  • Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institution's guidelines and be willing to undergo a bone marrow aspirate and/or biopsy at screening, during and at the end of therapy on this study.

Exclusion Criteria:

  1. History of severe hypersensitivity reactions to any ingredient of study treatment and/or their excipients.
  2. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment.
  3. High-risk patients for Tumor Lysis Syndrome according to Cairo et al 2010 criteria or local guidelines.
  4. Impaired cardiac function or clinically significant cardiac disease, or history or current diagnosis of ECG abnormalities indicating significant risk of safety including any of the following:

    1. Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker
    2. Any history of clinical important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, significant hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age
    4. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment
    5. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study.
    6. Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] <50%)
    7. Symptomatic congestive heart failure (New York Heart Association ≥ 3)
    8. Findings observed in the baseline cardiac MRI that might reflect an increased risk for cardiac adverse events.
  5. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior to start of study treatment. If thrombopoietin mimetics or erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
  6. For AML patients: Peripheral blast counts > 25,000 blasts / mm3. Patients can receive hydroxyurea to control the peripheral blast counts as long as hydroxyurea can be stopped at least 24 hours prior to obtaining PD biomarkers at screening/baseline. Hydroxyurea can be restarted after sampling if clinically indicated to control blasts prior to the start of study treatment markers.
  7. For patients with R/R NHL and R/R MM:

    • Absolute Neutrophil count < 1.0 x 109/L
    • Platelets count < 50 x 109/ L
    • Hemoglobin < 8 g/dl
  8. Autologous stem cell transplant within 3 months before the first dose of study treatment.
  9. Patients who have undergone a prior allogeneic stem cell transplant before the first dose of study treatment.
  10. History of or current interstitial lung disease or pneumonitis grade ≥ 2.
  11. Impaired hepatic and renal function defined as:

    • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN)
    • Bilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
    • Creatinine clearance <50 mL/min (calculated using Cockroft-Gault formula, or measured).
  12. Lipase >1.5 x ULN or serum amylase >1.5 x ULN and no history of pancreatitis.
  13. Increased cardiac troponin above the manufacturer's 99th percentile upper reference limit for local assay at screening

Other protocol-defined inclusion/exclusion criteria may apply


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04702425


Contacts
Layout table for location contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
Layout table for location information
United States, Texas
University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr Recruiting
Houston, Texas, United States, 77030
Contact    713-745-3246      
Principal Investigator: Naval Daver         
Belgium
Novartis Investigative Site Recruiting
Gent, Belgium, 9000
Finland
Novartis Investigative Site Recruiting
HUS, Finland, FIN-00029
Germany
Novartis Investigative Site Recruiting
Heidelberg, Germany, 69120
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Israel
Novartis Investigative Site Recruiting
Tel Aviv, Israel, 6423906
Italy
Novartis Investigative Site Recruiting
Rozzano, MI, Italy, 20089
Japan
Novartis Investigative Site Recruiting
Sunto Gun, Shizuoka, Japan, 411 8777
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Spain
Novartis Investigative Site Recruiting
Santander, Cantabria, Spain, 39008
Novartis Investigative Site Recruiting
Salamanca, Castilla Y Leon, Spain, 37007
Sponsors and Collaborators
Novartis Pharmaceuticals
Layout table for additonal information
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04702425    
Other Study ID Numbers: CVOB560A12101
First Posted: January 8, 2021    Key Record Dates
Last Update Posted: December 19, 2022
Last Verified: December 2022

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Phase Ib, BHLRM, VOB560, MIK665, NHL, AML, MM, Bcl2, Mcl1
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Leukemia, Myeloid
Multiple Myeloma
Neoplasms, Plasma Cell
Leukemia, Myeloid, Acute
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders