Trial Title:
A Study of Valemetostat Tosylate (DS-3201b) with Atezolizumab and Bevacizumab in HCC
NCT ID:
NCT06294548
Condition:
Hepatocellular Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Bevacizumab
Atezolizumab
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Valemetostat
Description:
Valemetostat is an inhibitor of the enzymes enhancer of zeste homolog 1 (EZH1) and
enhancer of zeste homolog 2 (EZH2).
Arm group label:
Phase 1b: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Arm group label:
Phase II: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Other name:
Valemetostat tosylate
Other name:
Valemetostat (DS-3201)
Intervention type:
Drug
Intervention name:
Atezolizumab
Description:
Atezolizumab is commercially available. Atezolizumab combined with bevacizumab is
approved for frontline treatment of advanced HCC based on IMbrave150 clinical trial. It
will be administered as per the package insert and institutional standards.
Arm group label:
Phase 1b: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Arm group label:
Phase II: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Intervention type:
Drug
Intervention name:
Bevacizumab
Description:
Bevacizumab is commercially available. Bevacizumab combined with atezolizumab is approved
for frontline treatment of advanced HCC based on IMbrave150 clinical trial. It will be
administered as per the package insert and institutional standards.
Arm group label:
Phase 1b: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Arm group label:
Phase II: Valemetostat + Atezolizumab 1200 mg + Bevacizumab 15 mg/kg
Summary:
This is a phase Ib/II, dose escalation and dose expansion study of valemetostat (DS-3201)
with atezolizumab and bevacizumab in patients advanced Hepatocellular carcinoma (HCC) who
did not receive prior systemic therapy for advanced HCC.
Detailed description:
Patients will be started on valemetostat (DS-3201) with atezolizumab and bevacizumab,
restaging scans will be performed every 9 weeks. The treatment will be continued until
progressive disease (PD), unacceptable toxicity or consent withdrawal. Paired research
biopsies will be performed.
This study will enroll up to approximately 45-patients at UAB. It is estimated 2 patients
will be enrolled per month over up to 36 months period.
Patients will receive valemetostat (DS-3201) orally daily at their assigned dose level,
plus atezolizumab 1200 mg intravenously (IV) on day 1, and bevacizumab 15 mg/kg IV on day
1 of each cycle. Each cycle is 21 days. Atezolizumab and bevacizumab will be administered
based on institutional guidelines and practice at the FDA approved dosages and intervals
for advanced HCC. Valemetostat should be taken immediately prior to the start of
atezolizumab and bevacizumab infusion on day 1 of each cycle.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Subjects must meet all the following criteria to be eligible for enrollment into the
study:
1. Sign and date the informed consent form (ICF), prior to the start of any
study-specific qualification procedures.
2. Subjects ≥18 years of age or the minimum legal adult age (whichever is greater) at
the time the ICF is signed
3. HCC diagnosis confirmed by histology/cytology or clinically by American Association
for Study of Liver Diseases (AASLD) 36 criteria in cirrhotic patients.
4. At least one measurable untreated lesion per RECIST v1.1 (see Section 12). Patients
who received prior liver directed therapy (ie., Trans arterial chemoembolization
[TACE], Y-90, liver directed radiation etc.) are eligible provided the target
lesion(s) have not been previously treated with liver directed therapy or the target
lesion(s) within the field of local therapy have subsequently progressed in
accordance with RECIST v1.1 (See Section 12)
5. Locally advanced, metastatic, or unresectable disease.
6. No prior systemic therapy for advanced HCC.
7. Child Pugh Class A.
8. Barcelona Clinic Liver Cancer (BCLC) Stage B (not amenable to liver directed
therapy) or Stage C.
9. ECOG Performance Status (PS) 0 or 1.
10. The following laboratory values obtained ≤ 28 days prior to registration. Local
laboratory data must meet the following criteria at both Screening and prior to
dosing on the planned Cycle 1 Day 1 visit to confirm relatively preserved organ
function:
- Absolute neutrophil count (ANC) ≥1500/mm3
- Platelet count 100,000/mm3 (platelet transfusion is not allowed within 14 days
prior to screening assessment).
- Hemoglobin (Hgb) 9.0 g/dL (red blood cell transfusion is not allowed within 14
days prior to screening assessment).
- Total bilirubin (TBIL) ≤1.5 x ULN.
- ALT and AST ≤3 x ULN
- For patients not receiving therapeutic anticoagulation INR or aPTT ≤2 x ULN
- Creatinine clearance ≥40 mL/min (measured by the Cockcroft-Gault equation)
11. If the subject is a female of childbearing potential, she must have a negative serum
pregnancy test at Screening and must be willing to use highly effective birth
control, as detailed in Section 4.4, upon enrollment, during the Treatment Period,
and for 6 months, following the last dose of study drug. A female is considered of
childbearing potential following menarche and until becoming postmenopausal (no
menstrual period for a minimum of 12 months) unless permanently sterile (undergone a
hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at
least 1 month before the first dose of study drug or confirmed by follicle
stimulating hormone (FSH) test >40 mIU/mL and estradiol <40 pg/mL (<140 pmol/L).
If male with partner of childbearing potential, the subject must be surgically
sterile or willing to use highly effective birth control (Section 4.4) upon
enrollment, during the Treatment Period, and for 6 months following the last dose of
study drug.
Female subjects must not donate, or retrieve for their own use, ova from the time of
screening and throughout the study treatment period, and for at least 6months after
the final study drug administration.
Male subjects must not freeze or donate sperm starting at Screening and throughout
the study period, and for at least 6 months after the final study drug
administration.
12. Provide informed written consent ≤28 days prior to registration.
13. Willing to return to enrolling institution for follow-up (during the Active
Monitoring Phase of the study).
Note: During the Active Monitoring Phase of a study (i.e., active treatment),
participants must be willing to return to the consenting institution for follow-up.
14. Willing to provide mandatory tissue specimens and blood specimens for correlative
research purposes (see Section 10).
15. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other
than alopecia) not yet resolved to NCI-CTCAE v 5.0, Grade ≤1 or Baseline.
Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no
worsening to > Grade 2 for at least 3 months prior to enrollment and managed with
standard of care treatment), which the Investigator deems related to previous anticancer
therapy, composed of the following:
1. Chemotherapy-induced neuropathy.
2. Fatigue.
3. Residual toxicities from prior immunotherapy treatment: Grade 1 or 2
endocrinopathies, which may include the following:
- Hypothyroidism/ hyperthyroidism.
- Type I diabetes.
- Hyperglycemia.
- Adrenal insufficiency.
- Adrenalitis.
- Skin hypopigmentation (vitiligo).
Exclusion Criteria:
Subjects who meet any of the following criteria will be disqualified from entering the
study:
1. Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn
are unknown:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate
contraception
2. Liver directed therapy (Trans arterial chemoembolization [TACE], Y-90, liver
directed radiation, etc.) ≤ 28 days prior to registration.
3. Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens.
4. Uncontrolled or significant cardiovascular disease, including the following:
- Evidence of prolongation of QT/QTc interval (eg, repeated episodes of QT
corrected for heart rate using Fridericia's method [QTcF] >470 ms) (average of
triplicate determinations)
- Myocardial infarction within 6 months prior to Screening
- Uncontrolled angina pectoris within 6 months prior to Screening
- New York Heart Association (NYHA) Class 3 or 4 congestive heart failure
- Inadequately controlled hypertension (defined as systolic blood pressure ≥150
mmHg and/or diastolic blood pressure >100 mmHg, based on average ≥3 blood
pressure readings on ≥2 sessions. Anti-hypertensive therapy to achieve these
parameters is allowed.
5. Prior malignancy active within the previous 3 years except for locally curable
cancer that is currently considered as cured, such as cutaneous basal or squamous
cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an
incidental histological finding of prostate cancer.
6. History of treatment with other EZH inhibitors
7. Current use of moderate or strong cytochrome P450 (CYP)3A inducers, and strong CYP3A
and/or P-gp inhibitors in dose escalation phase (See Table 11).
8. Immunocompromised patients and patients known to be Human immunodeficiency virus
(HIV) positive and currently receiving antiretroviral therapy or known acquired
immunodeficiency syndrome.
9. Regarding hepatitis B, patients must meet the following criteria to be eligible:
1. Patients with Hepatitis B (positive HBs antigen test) have an HBV-DNA Viral
Load <2000 IU/mL off treatment or on oral antiviral therapy for at least 4
weeks and during the participation in the study.
2. For patients at high-risk of Hepatitis B reactivation: Patients with contact to
the Hepatitis B virus (positive HBc antibody) that did not develop immunity
(negative HBs antibody) must have an HBV-DNA Viral Load <100 IU/mL on oral
antiviral therapy for at least 4 weeks and during the participation in the
study.
10. Patient has active Hepatitis C. Active Hepatitis C is defined by a positive Hep C Ab
result and quantitative HCV RNA results greater than the lower limits of detection
of the assay.
11. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
requiring treatment with intravenous antibiotics, antivirals, or antifungals. Note:
Subjects with localized fungal infections of skin or nails are eligible.
12. A medical history or complication considered inappropriate for participation in the
study, or a serious physical or psychiatric disease, the risk of which may be
increased by participation in the study in the investigator's opinion.
13. Psychological, social, familial, or geographical factors or substance abuse that
would prevent regular follow-up to be compliant with the protocol.
14. History of hemoptysis (≥2.5 mL of bright red blood per episode) within 1 month prior
to initiation of study treatment
15. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)
16. Current or recent (within 10 days of first dose of study treatment) use of aspirin
(> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and
cilostazol.
17. Current or recent (within 10 days prior to study treatment start) use of full-dose
oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed
to prophylactic) purpose. Prophylactic anticoagulation for the patency of venous
access devices is allowed provided the activity of the agent results in an INR < 1.5
x ULN and aPTT is within normal limits within 14 days prior to initiation of study
treatment. Prophylactic use of low molecular-weight heparin (i.e., enoxaparin 40
mg/day) is allowed.
18. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 3 days prior to the first dose of bevacizumab.
19. History of abdominal or tracheoesophageal fistula, gastrointestinal (GI)
perforation, or intra-abdominal abscess within 6 months prior to initiation of study
treatment
20. History of intestinal obstruction and/or clinical signs or symptoms of GI
obstruction including sub-occlusive disease related to the underlying disease or
requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
within 6 months prior to initiation of study treatment. Patients with signs/symptoms
of sub-/occlusive syndrome/intestinal obstruction at time of initial diagnosis may
be enrolled if they had received definitive (surgical) treatment for symptom
resolution.
21. Evidence of abdominal free air that is not explained by paracentesis or recent
surgical procedure.
22. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
23. Metastatic disease that involves major airways or blood vessels, or centrally
located mediastinal tumor masses (< 30 mm from the carina) of large volume Patients
with vascular invasion of the portal or hepatic veins may be enrolled.
24. History of intra-abdominal inflammatory process within 6 months prior to initiation
of study treatment, including but not limited to peptic ulcer disease,
diverticulitis, or colitis
25. Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior
to initiation of study treatment, except palliative radiotherapy to bone lesions
within 7 days prior to initiation of study treatment
26. Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to initiation of study treatment, or abdominal surgery, abdominal
interventions or significant abdominal traumatic injury within 60 days prior to
initiation of study treatment or anticipation of need for major surgical procedure
during the course of the study or non-recovery from side effects of any such
procedure
27. Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID).
Occasional use of NSAIDs for the symptomatic relief of medical conditions such as
headache or fever is allowed.
28. Known fibrolamellar carcinoma (FLC), sarcomatoid HCC, or combined
hepatocellular-cholangiocarcinoma (cHCC-CC)
29. Patients with untreated or incompletely treated varices with bleeding or high-risk
for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all
size of varices (small to large) must be assessed and treated per local standard of
care prior to enrollment. Patients who have undergone an EGD within 6 months of
prior to initiation of study treatment do not need to repeat the procedure.
30. History of allogenic organ transplantation.
31. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis
syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,
rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to
this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
32. History of leptomeningeal carcinomatosis or intracranial metastases
33. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
34. Current or prior use of immunosuppressive medication ≤ 14 days prior to
registration. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
35. Receipt of live attenuated vaccine ≤30 days prior to registration. Note: Patients,
if enrolled, should not receive live vaccine whilst on study treatment and up to 30
days after the last dose of study treatment.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Alabama at Birmingham
Address:
City:
Birmingham
Zip:
35294
Country:
United States
Contact:
Last name:
Margaret Thomas, MPH
Email:
margaretannthomas@uabmc.edu
Contact backup:
Last name:
Mehmet S Akce, MD
Start date:
December 31, 2024
Completion date:
June 28, 2028
Lead sponsor:
Agency:
University of Alabama at Birmingham
Agency class:
Other
Source:
University of Alabama at Birmingham
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06294548