Phase 1/2 Study of VIP152, Venetoclax, and Prednisone (VVIP) in Relapsed/Refractory Lymphoid Malignancies

• Status: Not yet recruiting
• Trial end date: 2025-03-10
• Target enrollment: 0
• Participant gender: All

Summary

Background:

• High unmet medical need for relapsed/refractory non-Hodgkin lymphoma (NHL) after exhausting chemotherapy and/or chemo- immunotherapy regimens

• Targeted therapies aimed at disrupting cell death pathway in hematologic malignancies are emerging and showing significant activity in both the relapsed and first-line settings

• VIP152 is a selective inhibitor of PTEFb/CDK9 and is expected to show efficacy in tumor indications that overexpress MYC and MCL-1. VIP152 monotherapy has demonstrated a mild toxicity profile and preliminary efficacy in Phase 1 studies in advanced cancer

• The combination of VIP152 with venetoclax and prednisone (VVIP) targets major celldeath pathways in lymphoid malignancies (BCL-2 and MCL-1) and may overcome chemo-resistance and/or single drug resistance to venetoclax

Objectives:

• Phase 1: To determine the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and the safety and toxicity profile of the combination of VIP152 with venetoclax and prednisone (VVIP) in relapsed/refractory lymphoid malignancies

• Phase 2: To determine the complete response (CR) rate of the combination of VIP152 with venetoclax and prednisone (VVIP) in R/R lymphoid malignancies

Eligibility:

• Women and men >= 18 years of age

• ECOG performance status of <= 2

• Histologically or cytologically confirmed relapsed and/or refractory NHL

• Adequate organ function unless dysfunction secondary to disease effect

Design:

• Open-label, single-center, non-randomized Phase 1/2 study

• Phase 1: Standard 3 + 3 design will be used to determine the MTD and RP2D of doseescalated VIP152 and venetoclax with fixed dose prednisone in relapsed/refractory lymphoid malignancies

• Phase 2: Expansion cohorts of defined aggressive NHL subtypes will be treated at the RP2D to determine the ORR and CR rate in these disease groups

• Up to 24 cycles of combination targeted therapy given in 21-day cycles with the option to stop therapy after 12 cycles if in CR following cycles 6 and/or 12 of therapy.

• To explore all dose levels of VIP152 and venetoclax in combination prednisone (VVIP) in R/R NHL in the Phase 1 study (24 participants max) and to assess the CR rate in 3 defined cohorts of aggressive NHL in a Phase 2 dose expansion (3 cohorts x 29 participants = 87 participants max) at RP2D, the accrual ceiling will be set at 130 participants

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Prednisone; Venetoclax

Criteria

• INCLUSION CRITERIA:

Participants must have a histologically or cytologically confirmed lymphoid malignancy as listed below, confirmed by the Laboratory of Pathology, NCI, as follows:

• R/R MYC-rearranged DLBCL/HGBCL (MYC aberration must be confirmed by NCI Laboratory of Pathology to enroll)

• R/R non-GCB DLBCL without MYC-rearrangement (COO and non- MYC aberration must be confirmed by NCI Laboratory of Pathology to enroll. COO determination at enrollment will utilize immunohistochemistry and Han s algorithm

• R/R PTCL (PTCL-NOS, PTCL-TFH, follicular TCL, AITL, ATLL, ALK+ ALCL and ALK- ALCL per 2016 WHO classification)

Relapsed and/or refractory disease, as defined below:

• Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 2 prior systemic therapies, 1 or more which includes an anthracycline and anti-CD20 targeting agent

• PTCL: relapsed after and/or refractory to at least 2 prior systemic therapies, 1 or more which includes an anthracycline (and a brentuximab vedotin-containing regimen for participants with ALK+ or ALK- ALCL)

Must have evaluable disease by clinical exam (i.e., palpable lymphadenopathy, measurable skin lesions, etc.), laboratory assessment (i.e., disease involvement of bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or imaging (measurable lymph nodes, masses, or bony lesions on CT or MRI and/or evaluable FDGavid lesions on PET).

NOTE: Lesions that have been irradiated cannot be included in the tumor assessment

unless unequivocal tumor progression has been documented in these lesions after

radiation therapy.

Age >18 years

ECOG performance status <2

Adequate organ and marrow function as defined below unless dysfunction is secondary to disease:

Absolute neutrophil count >=1,000/mcL

Hemoglobin >=8 g/dL

Platelets >=75,000/mcL

INR <=1.5 X institutional upper limit of normal (ULN) for

participants not receiving therapeutic anticoagulation

PTT/aPTT <1.5 X institutional ULN normal except if the aPTT is elevated because of a positive Lupus Anticoagulant

Total bilirubin <=1.5 X institutional ULN (or <=3 X institutional ULN for participants with documented Gilberts syndrome)

AST(SGOT)/ALT(SGPT) =<2.5 X institutional ULN

Serum creatinine <= 2.0 mg/dL

OR

Creatinine clearance >=40 mL/min/1.73 m2 for participants with creatinine levels above 2 mg/dL

Cr Cl will be calculated with the use of the 24-hour creatinine clearance or modified

Cockcroft-Gault equation (eCCR; with the use of ideal body mass [IBM] instead of mass):

(140 Age) x IBM (kg) (SqrRoot) [0.85 if female]/72 x serum creatinine (mg/dL)

RBC transfusions and use of G-CSF will be allowed in order to meet eligibility parameters.

• Total bilirubin must be <3 X institutional ULN for eligibility even if secondary to disease.

• AST(SGOT)/ALT(SGPT) must be <5 X institutional ULN for eligibility even if secondary to disease.

• Creatinine clearance must be >30 mL/min for eligibility even if secondary to disease.

Negative serum or urine pregnancy test must be obtained within 7 days before the first

dose of study drug in women of childbearing potential. Postmenopausal women, as

defined below, are allowed to enroll without a pregnancy test:

• Age >50 years with amenorrhea for at least 12 months or

• Age <=50 years with 6 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) level within postmenopausal range (>40 mIU/mL) OR

• Permanently sterilized women (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, uterine ablation)

Women and men of reproductive potential must agree to use highly effective contraception when sexually active. This applies for the period between signing of the informed consent and 90 days after the last administration of study drug.

Highly effective contraception includes:

• Established use of oral, injected or implanted hormonal methods of contraception

• Placement of certain intrauterine devices (IUD) or intrauterine systems (IUS)

• Hysterectomy, oophorectomy, salpingectomy or vasectomy of the partner (provided that partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success)

In addition, participants must agree to use condoms.

Participants that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative hepatitis B and/or C viral load by polymerase chain reaction (PCR), and agree to additional monitoring.

Ability of participant to understand and the willingness to sign a written informed consent document.

Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 90 days after the last administration of study drug.

EXCLUSION CRITERIA:

The following restrictions apply to current or prior anti-cancer treatment, prior to the first dose of study drug:

• Participants who are actively receiving any other anti-cancer investigational agents.

• Any chemotherapy, targeted therapy, or anti-cancer antibodies within 2 weeks prior to the first dose of study drug

• Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug

• Prior allogeneic stem cell (or other organ) transplant within 6 months or any evidence of active graft-versus-host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug

• Not recovered (i.e., <= Grade 1 or baseline) from adverse events due to previously administered anti-cancer treatment, surgery, or procedure.

NOTE: Exceptions to this include events not considered to place the participant at unacceptable risk of participation in the opinion of the PI (e.g., alopecia).

Participants requiring the following agents within 14 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of venetoclax and VIP152 are excluded:

• Strong CYP3A inhibitors

• Strong CYP3A inducers

• Moderate CYP3A inhibitors (dose-escalation cohort only)

• Moderate CYP3A inducers (dose-escalation cohort only)

NOTE: Moderate CYP3A inhibitors and inducers should be used with caution for participants in the dose-expansion cohorts and an alternative medication used, whenever possible.

Known allergy to both xanthine oxidase inhibitors and rasburicase; or, known hypersensitivity to any of the study drugs

Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 2 weeks prior to first dose of study drug

HIV-positive participants

Active CMV infection as determined by a positive CMV PCR

Active SARs-CoV-2 infection based on PCR assay; prior SARs-CoV-2 infection allowed if completely recovered from infection and negative PCR testing

Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis; as well as active infection with HBV or HCV except as noted above in inclusion criteria

• Participants with occult (defined as positive total hepatitis B core antibody [HBcAb] and positive HBsAg) or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable.

• Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation

Malabsorption syndrome or other condition that precludes enteral route of administration

History of other active malignancy requiring therapy that could affect compliance with the protocol or interpretation of results

Symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia

Left ventricular ejection fraction (LVEF) < 45%

Clinically relevant findings on electrocardiogram (ECG) such as a second- or third degree AV block or prolongation of the QTc interval (Fridericia) over 470 msec (participants with AV block and pacemaker in place for >1 year and checked by a cardiologist within <6 months before the first dose of study drug, will not be excluded).

Uncontrolled intercurrent illness (including psychiatric) or social situations that may limit interpretation of results or that could increase risk to the participant