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)

• ClinicalTrials.gov Identifier: NCT04702425
• Recruitment Status: Active, not recruiting
• First Posted: January 8, 2021
• Last Update Posted: May 3, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 37 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: September 2, 2024
• Estimated Study Completion Date: September 2, 2024

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Locations

United States, Connecticut

Yale University School of Medicine Smilow Cancer Hospital

New Haven, Connecticut, United States, 06520

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Texas

Uni of TX MD Anderson Cancer Cntr UT MD Anderson Cancer Ctr

Houston, Texas, United States, 77030

Belgium

Novartis Investigative Site

Gent, Belgium, 9000

Finland

Novartis Investigative Site

HUS, Finland, FIN-00029

Germany

Novartis Investigative Site

Heidelberg, Germany, 69120

Novartis Investigative Site

Ulm, Germany, 89081

Hong Kong

Novartis Investigative Site

Hong Kong, Hong Kong

Israel

Novartis Investigative Site

Tel Aviv, Israel, 6423906

Italy

Novartis Investigative Site

Rozzano, MI, Italy, 20089

Japan

Novartis Investigative Site

Sunto Gun, Shizuoka, Japan, 411 8777

Korea, Republic of

Novartis Investigative Site

Seoul, Korea, Republic of, 03080

Spain

Novartis Investigative Site

Santander, Cantabria, Spain, 39008

Novartis Investigative Site

Salamanca, Castilla Y Leon, Spain, 37007

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04702425
• Other Study ID Numbers: CVOB560A12101
• First Posted: January 8, 2021
• Last Update Posted: May 3, 2023
• Last Verified: May 2023

• 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:

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