Clinical trial NCT04702425: 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)
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Non-Hodgkin Lymphoma (NHL)
Acute Myeloid Leukemia (AML)
Multiple Myeloma (MM)
Keywords: Phase Ib, BHLRM, VOB560, MIK665, NHL, AML, MM, Bcl2, Mcl1
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-01-08
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study was 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.

Detailed description: This was an open-label, non-randomized multi-center phase Ib dose-escalation study with dose expansion arms in four different patient populations. Patients received VOB560 in combination with MIK665 in a once a week (QW) schedule over 21 days cycle. Less frequent dosing schedules could be explored based on emerging data. Patients were to be treated until disease progression or unacceptable toxicities occurred.

The study included a dose escalation part (Part 1) and a dose expansion part (Part 2).

The following escalation arms were planned:

* Arm A: relapsed/refractory (R/R) NHL and R/R MM
* Arm B: R/R AML There were 4 expansion arms planned. However, the expansion part of the study was not initiated.

Eligibility 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

Primary outcomes:
measure: Incidence and severity of AEs and SAEs, including changes in lab values, vital signs, and ECGs
timeFrame: at month 18
measure: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment with VOB560 and MIK665 in combination
timeFrame: at month 18
measure: Frequency of dose interruptions
timeFrame: at month 18
measure: Frequency of dose reductions
timeFrame: at month 18
measure: Dose intensities
timeFrame: at month 18
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: at month 18
measure: Complete Response (CR) rate (and rate of CR or sCR in R/R MM)
timeFrame: at month 18
measure: Best Overall Response (BOR)
timeFrame: at month 18
measure: Duration Of Response (DOR)
timeFrame: at month 18
measure: Progression Free Survival (PFS)
timeFrame: at month 18
measure: Area Under Curve (AUC) of VOB560
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Maximum Plasma Concentration (Cmax) ok VOB560
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Terminal elimination half-life (T1/2) of VOB560
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Clearance (CL) of VOB560
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Apparent volume of distribution (Vz) of VOB560
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Area Under Curve (AUC) of MIK665
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Maximum Plasma Concentration (Cmax) ok MIK665
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Terminal elimination half-life (T1/2) of MIK665
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Clearance (CL) of MIK665
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
measure: Apparent volume of distribution (Vz) of MIK665
timeFrame: At the end of Cycle 6 (each cycle is 21 days)
Other outcomes:
Locations:
city: Houston
country: United States
facility: Uni of TX MD Anderson Cancer Cntr UT MD Anderson Cancer Ctr
state: Texas
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: HUS
country: Finland
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Sunto Gun
country: Japan
facility: Novartis Investigative Site
state: Shizuoka
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Santander
country: Spain
facility: Novartis Investigative Site
state: Cantabria
Study officials:
References: