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)

Acute Myeloid Leukemia (AML) Clinical Trial

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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04702425
• Other study ID #: CVOB560A12101
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: June 23, 2021
• Est. completion date: July 30, 2024

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 37
• Est. completion date: July 30, 2024
• Est. primary completion date: July 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Lymphoma, Non-Hodgkin
• Multiple Myeloma
• Multiple Myeloma (MM)
• Neoplasms, Plasma Cell
• Non-Hodgkin Lymphoma (NHL)

Intervention

Drug:
• VOB560
Powder for concentrate for solution for infusion
• MIK665
Concentrate for solution for infusion

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Gent
Finland	Novartis Investigative Site	HUS
Hong Kong	Novartis Investigative Site	Hong Kong
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Sunto Gun	Shizuoka
Korea, Republic of	Novartis Investigative Site	Seoul
Spain	Novartis Investigative Site	Santander	Cantabria
United States	Uni of TX MD Anderson Cancer Cntr UT MD Anderson Cancer Ctr	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Finland,  Hong Kong,  Israel,  Italy,  Japan,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of AEs and SAEs, including changes in lab values, vital signs, and ECGs	Month 18 is assumed to be study end	at month 18
Primary	Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment with VOB560 and MIK665 in combination	Month 18 is assumed to be study end	at month 18
Primary	Frequency of dose interruptions	Month 18 is assumed to be study end	at month 18
Primary	Frequency of dose reductions	Month 18 is assumed to be study end	at month 18
Primary	Dose intensities	Month 18 is assumed to be study end	at month 18
Secondary	Overall Response Rate (ORR)	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	at month 18
Secondary	Complete Response (CR) rate (and rate of CR or sCR in R/R MM)	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	at month 18
Secondary	Best Overall Response (BOR)	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	at month 18
Secondary	Duration Of Response (DOR)	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	at month 18
Secondary	Progression Free Survival (PFS)	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	at month 18
Secondary	Area Under Curve (AUC) of VOB560	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Maximum Plasma Concentration (Cmax) ok VOB560	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Terminal elimination half-life (T1/2) of VOB560	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Clearance (CL) of VOB560	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Apparent volume of distribution (Vz) of VOB560	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Area Under Curve (AUC) of MIK665	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Maximum Plasma Concentration (Cmax) ok MIK665	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Terminal elimination half-life (T1/2) of MIK665	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Clearance (CL) of MIK665	PK parameter	At the end of Cycle 6 (each cycle is 21 days)
Secondary	Apparent volume of distribution (Vz) of MIK665	PK parameter	At the end of Cycle 6 (each cycle is 21 days)