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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Non-Hodgkin Lymphoma; NHL; Hematologic Malignancies; Lymphoid Malignancies
• Intervention / Treatment: 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

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

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

• Participants must have a histologically or cytologically confirmed lymphoid malignancy as listed below, confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), as follows:

  • Refractory/relapsed (R/R) MYC-rearranged diffuse large B-cell lymphoma (DLBCL)/High-grade B-cell lymphoma (HGBCL) (MYC aberration must be confirmed by NCI Laboratory of Pathology to enroll)
  • R/R non-germinal center B-cell (non-GCB) DLBCL without MYC-rearrangement (Cell of origin (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 Peripheral T-cell lymphoma (PTCL-not otherwise specified (NOS), PTCL-T follicular helper (TFH), follicular T-cell lymphoma (TCL), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), anaplastic lymphoma kinase (ALK)+ anaplastic large-cell lymphoma (ALCL) and ALK- ALCL per 2016 World Health Organization (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-cluster of differentiation 20 (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 computed tomography (CT) or magnetic resonance imaging (MRI) and/or evaluable FD-Gavid lesions on positron emission tomography (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
• Eastern Cooperative Oncology Group (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
  • International normalized ratio (INR) <=1.5 X institutional upper limit of normal (ULN) for participants not receiving therapeutic anticoagulation
  • Partial thromboplastin time (PTT)/activated partial thromboplastin time (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 Gilbert's syndrome)
  • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)(SGOT)/Alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT)*** <= 2.5 X institutional ULN
  • Serum creatinine <= 2.0 mg/dL

OR

--Creatinine clearance**** >= 40 mL/min/1.73 m^2 for participants with creatinine levels above 2 mg/dL

Creatinine clearance (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) x [0.85 if female] / 72 x serum creatinine (mg/dL)

*Red blood cell (RBC) transfusions and use of granulocyte colony-stimulating factor (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 individuals of childbearing potential. Postmenopausal individuals, 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 (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, uterine ablation)
      • Individuals 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 individual 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 (HBcAb), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCVAb) 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.
• Nursing participants must be willing to discontinue nursing 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 principal investigator (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 cytochrome P450, family 3, subfamily A (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 cytomegalovirus (CMV) infection as determined by a positive CMV polymerase chain reaction (PCR)
• Active severe acute respiratory syndrome coronavirus 2 (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 hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) except as noted above in inclusion criteria

  • Participants with occult or prior HBV infection (defined as positive hepatitis B surface antigen (HBsAg) or positive hepatitis B core antibody (HBcAb)) may be included if HBV deoxyribonucleic acid (DNA) is undetectable (i.e., none detected in copies/mL or IU/mL). These individuals must be willing to undergo HBV DNA testing during treatment and in surveillance for at least 12 months after completion of study therapy.
  • 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 heart-rate corrected QT interval (Qtc) (Fridericia) over 470 msec (participants with atrioventricular (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1/Phase 1: Arm 1 Dose Escalation; 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.	Device: Vysis LSI MYC Break Apart Rearrangement Probe Kit; MYC rearrangement fluorescence in situ hybridization (FISH) testing is performed using the Vysis LSI MYC Break Apart Rearrangement Probe (Abbott Molecular, Inc.) in the Chromosome Pathology Section, Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI). This kit is not Food and Drug Administration (FDA) approved. It is being used as a treatment determining in-vitro diagnostic device in this study.; Drug: Venetoclax; Dose Escalation: Administered orally, days 1-10, per specified dose level; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity. Dose Expansion: Administered orally, days 1-10, at the recommended phase 2 dose (RP2D); every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity; Other Names: Venclexta; Venclyxto; Drug: VIP152; Dose Escalation: Administered intravenously, days 2 and 9, per specified dose level; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity. Dose Expansion: Administered intravenously, days 2 and 9, at the recommended phase 2 dose (RP2D); every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity.; Other Names: Enitociclib; Drug: Prednisone; Administered orally, days 1-10, at a dose of 100 mg; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity; Other Names: Deltasone; Prednisone Intensol; Rayos; Diagnostic test: PET; Screening, pre-cycle 7, pre-cycle 13, and at end-of-treatment (post-cycle 24).; Other Names: Positron emission imaging; Diagnostic test: EKG; Screening; Other Names: Electrocardiogram; Diagnostic test: ECHO; Screening; Other Names: Echocardiogram; Diagnostic test: CT neck chest, abdomen, and pelvis; Screening, pre-cycle 2, pre-cycle 3, pre-cycle 5, pre-cycle 7, pre-cycle 9, pre-cycle 11, pre-cycle 13, pre-cycle 15, pre-cycle 17, pre-cycle 19, pre-cycle 21, pre-cycle 23, and at end-of-treatment (post cycle 24).; Other Names: Computed tomography neck chest, abdomen, and pelvis; Diagnostic test: MRI; As indicated. Screening, pre-cycle 2, pre-cycle 3, pre-cycle 5, pre-cycle 7, pre-cycle 9, pre-cycle 11, pre-cycle 13, pre-cycle 15, pre-cycle 17, pre-cycle 19, pre-cycle 21, pre-cycle 23, and at end-of-treatment (post cycle 24).; Other Names: Magnetic resonance imaging; Procedure: Bone marrow aspiration/Biopsy; Baseline, post-cycle 6, post-cycle 12, and at end-of-treatment (post-cycle 24).; Other Names: BM aspiration/Bx
Experimental: Cohort 2/Phase 2: Arm 2 Dose Expansion; Enitociclib (VIP152), Venetoclax and prednisone (VVIP) - VIP152 and venetoclax at the recommended phase II dose (RP2D) with prednisone at fixed doses.	Device: Vysis LSI MYC Break Apart Rearrangement Probe Kit; MYC rearrangement fluorescence in situ hybridization (FISH) testing is performed using the Vysis LSI MYC Break Apart Rearrangement Probe (Abbott Molecular, Inc.) in the Chromosome Pathology Section, Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI). This kit is not Food and Drug Administration (FDA) approved. It is being used as a treatment determining in-vitro diagnostic device in this study.; Drug: Venetoclax; Dose Escalation: Administered orally, days 1-10, per specified dose level; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity. Dose Expansion: Administered orally, days 1-10, at the recommended phase 2 dose (RP2D); every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity; Other Names: Venclexta; Venclyxto; Drug: VIP152; Dose Escalation: Administered intravenously, days 2 and 9, per specified dose level; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity. Dose Expansion: Administered intravenously, days 2 and 9, at the recommended phase 2 dose (RP2D); every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity.; Other Names: Enitociclib; Drug: Prednisone; Administered orally, days 1-10, at a dose of 100 mg; every 21 days for up to 24 cycles, or until disease progression or unacceptable toxicity; Other Names: Deltasone; Prednisone Intensol; Rayos; Diagnostic test: PET; Screening, pre-cycle 7, pre-cycle 13, and at end-of-treatment (post-cycle 24).; Other Names: Positron emission imaging; Diagnostic test: EKG; Screening; Other Names: Electrocardiogram; Diagnostic test: ECHO; Screening; Other Names: Echocardiogram; Diagnostic test: CT neck chest, abdomen, and pelvis; Screening, pre-cycle 2, pre-cycle 3, pre-cycle 5, pre-cycle 7, pre-cycle 9, pre-cycle 11, pre-cycle 13, pre-cycle 15, pre-cycle 17, pre-cycle 19, pre-cycle 21, pre-cycle 23, and at end-of-treatment (post cycle 24).; Other Names: Computed tomography neck chest, abdomen, and pelvis; Diagnostic test: MRI; As indicated. Screening, pre-cycle 2, pre-cycle 3, pre-cycle 5, pre-cycle 7, pre-cycle 9, pre-cycle 11, pre-cycle 13, pre-cycle 15, pre-cycle 17, pre-cycle 19, pre-cycle 21, pre-cycle 23, and at end-of-treatment (post cycle 24).; Other Names: Magnetic resonance imaging; Procedure: Bone marrow aspiration/Biopsy; Baseline, post-cycle 6, post-cycle 12, and at end-of-treatment (post-cycle 24).; Other Names: BM aspiration/Bx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Complete Response (CR) Rate	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).	24 cycles (i.e., 72 weeks)
Phase 1: Number of Solicited and/or Non-solicited Non-serious Adverse Events (AE's) With Grade	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.	Up to 18 weeks.
Phase 1: Number of Solicited and/or Unsolicited Serious Adverse Events (SAE's) With Grade	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.	Up to 18 weeks.
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D)	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.	First 22 days (i.e., cycle 1, day 1 to cycle 2, day 1 pre-dose)
Phase 1: Number of Participants With Grade 4 Neutropenia Dose-Limiting Toxicity (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.	First 22 days (i.e., cycle 1, day 1 to cycle 2, day 1 pre-dose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Progression-free Survival (PFS)	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.	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
Phase 1: Time to Response (TTR)	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.	Time from the date of study enrollment during therapy, after completion of therapy from initiation of therapy to first response, up to 5 months
Phase 1: Duration of Response (DOR)	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.	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
Phase 1: Overall Response Rate (ORR)	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.	24 cycles (i.e., 72 weeks)
Phase 1: Event-free Survival (EFS)	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).	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
Phase 1: Overall Survival (OS)	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.	Assessed from the date of study enrollment until death from any cause, or last follow-up, whichever occurs first, up to a maximum of 32 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. 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.	24 cycles (i.e., 72 weeks)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Christopher J Melani, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Frigault MM, Mithal A, Wong H, Stelte-Ludwig B, Mandava V, Huang X, Birkett J, Johnson AJ, Izumi R, Hamdy A. Enitociclib, a Selective CDK9 Inhibitor, Induces Complete Regression of MYC+ Lymphoma by Downregulation of RNA Polymerase II Mediated Transcription. Cancer Res Commun. 2023 Nov 9;3(11):2268-2279. doi: 10.1158/2767-9764.CRC-23-0219.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2023
• Primary Completion (Actual): July 22, 2024
• Study Completion (Actual): December 16, 2025

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: May 11, 2022
• First Posted (Actual): May 12, 2022

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Dose Finding; Small Molecule
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hemic and Lymphatic Diseases; Hematologic Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Diagnostic Techniques, Surgical; Tomography; Diagnostic Imaging; Pregnadienediols; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Electrodiagnosis; Cardiac Imaging Techniques; Ultrasonography; Image Interpretation, Computer-Assisted; Image Enhancement; Photography; Tomography, Emission-Computed; Radionuclide Imaging; Diagnostic Techniques, Radioisotope; Prednisone; Biopsy; Magnetic Resonance Imaging; venetoclax; Electrocardiography; Positron-Emission Tomography; Echocardiography
• Other Study ID Numbers: 10000633; 000633-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data will be available during the study and indefinitely. Genomic data will be available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data will be made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No