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

Phase 1

Active, not recruiting

Conditions: Non-Hodgkin Lymphoma
NHL
Hematologic Malignancies
Lymphoid Malignancies
Lymphoma

Interventions: Device: Vysis LSI MYC Break Apart Rearrangement Probe Kit
Drug: Venetoclax
Drug: VIP152
Drug: Prednisone
Diagnostic Test: PET
Diagnostic Test: EKG
Diagnostic Test: ECHO
Diagnostic Test: CT neck chest, abdomen, and pelvis
Diagnostic Test: MRI
Procedure: Bone marrow aspiration/Biopsy

Registration Number: NCT05371054

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Non-Hodgkin lymphomas are blood cancers that can be difficult to treat. They can also return after treatment. Examples include diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL). More effective treatments are needed for these diseases.

Objective:

To test the safety of a study drug (Enitociclib (VIP152) in combination with other drugs used to treat people with aggressive blood cancers.

Eligibility:

People aged 18 years or older diagnosed with DLBCL, PTCL, or related blood cancers. The cancers must have either not responded to treatment or returned after treatment.

Design:

Participants will undergo screening. They will have a physical exam with scans and blood and urine tests. They will have imaging scans and tests of their heart function. They may also provide a bone marrow aspiration or biopsy.

Participants may provide a saliva sample for deoxyribonucleic acid (DNA) testing.

Participants will receive study treatment in cycles. Each cycle is 21 days.

Participants will take two drugs by mouth at home once a day on days 1-10 of each cycle.

On days 2 and 9 they will come to the clinic to receive VIP152. This drug will be administered through a small plastic tube with a needle placed in a vein.

On day 11, participants will receive a fourth medication as an injection under the skin. They will rest and recover on days 12-21.

Screening tests will be repeated periodically throughout the study period.

Treatment will continue for up to 24 cycles.

Participants will have follow-up visits for up to 5 years.

Detailed Description: 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

* Enitociclib (VIP152) is a selective inhibitor of positive transcription elongation factor (PTEFb)/Cyclin-dependent kinase 9 (CDK9) and is expected to show efficacy in tumor indications that overexpress MYC and myeloid Cell Leukemia-1 (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 cell-death pathways in lymphoid malignancies (B-cell lymphoma 2 (BCL-2 and myeloid cell leukemia 1 (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

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 8

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1/Phase 1: Arm 1 Dose Escalation	Vysis LSI MYC Break Apart Rearrangement Probe Kit	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	Venetoclax	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	VIP152	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	Prednisone	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	ECHO	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 2/Phase 2: Arm 2 Dose Expansion	Vysis LSI MYC Break Apart Rearrangement Probe Kit	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 1/Phase 1: Arm 1 Dose Escalation	PET	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	EKG	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	CT neck chest, abdomen, and pelvis	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	Bone marrow aspiration/Biopsy	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 1/Phase 1: Arm 1 Dose Escalation	MRI	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at escalating doses with prednisone at fixed doses to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of VIP152 and venetoclax.
Cohort 2/Phase 2: Arm 2 Dose Expansion	Venetoclax	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	VIP152	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	Prednisone	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	PET	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	EKG	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	ECHO	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	CT neck chest, abdomen, and pelvis	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	MRI	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.
Cohort 2/Phase 2: Arm 2 Dose Expansion	Bone marrow aspiration/Biopsy	Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.

Primary Outcome Measures

Name	Time	Method
Phase 2: Complete Response (CR) Rate	24 cycles (i.e., 72 weeks)	CR rate is defined as the percentage of participants who meet criteria for complete response (CR) as measured by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Complete response is defined as target nodes/nodal masses that regress to \<1.5 cm in longest transverse diameter of a lesion (LDi).
Phase 1: Number of Solicited and/or Non-solicited Non-serious Adverse Events (AE's) With Grade	Up to 18 weeks.	Number of non-serious adverse events (AE's) with grade was assessed by the CTCAEv5.0. A non-serious adverse event is any untoward medical occurrence that does not meet seriousness criteria. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 if life-threatening.
Phase 1: Number of Solicited and/or Unsolicited Serious Adverse Events (SAE's) With Grade	Up to 18 weeks.	Number of serious adverse events (SAE's) with grade was assessed by the CTCAEv5.0. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is fatal.
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D)	First 22 days (i.e., cycle 1, day 1 to cycle 2, day 1 pre-dose)	The MTD/RP2D is the dose level at which no more than 1 of up to 6 participants experience dose limiting toxicity (DLT) during the DLT evaluation window(s), or the dose below that at which at least 2 (of ≤6) participants have DLT. A DLT (dose-limiting toxicity) is defined as a grade 3 or higher adverse event (AE) that occurs in the dose-escalation cohort within the first 22 days after initiation of VVIP (i.e., Cycle 1, Day 1 to Cycle 2, Day 1 pre-dose) and is considered related to study drug (i.e., VIP152, venetoclax, and/or prednisone) or a treatment delay of cycle 2 of \> 7 days for hematologic or nonhematologic toxicities.
Phase 1: Number of Participants With Grade 4 Neutropenia Dose-Limiting Toxicity (DLT)	First 22 days (i.e., cycle 1, day 1 to cycle 2, day 1 pre-dose)	A DLT (dose-limiting toxicity) is defined as a grade 3 or higher adverse event (AE) that occurs in the dose-escalation cohort within the first 22 days after initiation of VVIP (i.e., Cycle 1, Day 1 to Cycle 2, Day 1 pre-dose) and is considered related to study drug (i.e., VIP152, venetoclax, and/or prednisone) or a treatment delay of cycle 2 of \> 7 days for hematologic or nonhematologic toxicities.

Secondary Outcome Measures

Name	Time	Method
Phase 1: Progression-free Survival (PFS)	Assessed from date of study enrollment until time of disease relapse, disease progression, death, or last follow-up, whichever comes first, up to 8 months	PFS is defined as the duration of time from the date of study enrollment until the date of disease relapse, disease progression, death, or last follow-up, whichever occurs first, using the Kaplan-Meier method. Response was assessed by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Disease progression is defined as an increase of ≥ 50% from the product of the perpendicular diameter (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir of \>0.5 cm for lesions \<2 cm or \>1.0 cm for lesions \>2 cm.
Phase 1: Time to Response (TTR)	Time from the date of study enrollment during therapy, after completion of therapy from initiation of therapy to first response, up to 5 months	TTR is defined as the time from the start of the treatment until time of first objective response using the Kaplan-Meier method. Median, assessed during therapy and after completion of therapy from initiation of therapy to first response every (q)3, 4, 6 and 12 months for post-treatment years 1, 2, 3, and 4-5, respectively, for up to 5 years after the last participant has enrolled on study. Response was measured by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Complete response is target nodes/nodal masses that regress to \<1.5 cm in longest transverse diameter of a lesion. Partial response is ≥ 50% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) of up to 6 target measurable nodes and extranodal sites. Disease progression is an increase by ≥ 50% from progressive disease progression (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir.
Phase 1: Duration of Response (DOR)	Time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 months	DOR is defined as the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented using the Kaplan-Meier method. Response was measured by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Complete response is target nodes/nodal masses that regress to \<1.5 cm in longest transverse diameter of a lesion (LDi). Partial response is ≥ 50% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) of up to 6 target measurable nodes and extranodal sites. Disease progression is an increase by ≥ 50% from progressive disease progression (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir of \>0.5 cm for lesions \<2 cm or \>1.0 cm for lesions \>2 cm.
Phase 1: Overall Response Rate (ORR)	24 cycles (i.e., 72 weeks)	ORR is defined as the proportion of participants who meet criteria for complete response (CR) or partial response (PR) as measured by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Complete response is target nodes/nodal masses that regress to \<1.5 cm in longest transverse diameter of a lesion (LDi). Partial response is ≥ 50% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) of up to 6 target measurable nodes and extranodal sites.
Phase 1: Overall Survival (OS)	Assessed from the date of study enrollment until death from any cause, or last follow-up, whichever occurs first, assessed up to 5 years from study enrollment	OS is defined as the time from the date of study enrollment until death from any cause, or last follow-up, whichever occurs first, assessed using the Kaplan-Meier method.
Phase 1: Event-free Survival (EFS)	Assessed from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), death, or last follow-up, whichever occurs first, assessed up to 8 months	EFS is defined as the time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), death, or last follow-up, whichever occurs first, assessed using the Kaplan-Meier method. Disease progression is an increase by ≥ 50% from progressive disease progression (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir of \>0.5 cm for lesions \<2 cm or \>1.0 cm for lesions \>2 cm as assessed by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL).