IRB Study Number 24-722
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Part 1 Dose-escalation Phase: To assess the safety and tolerability of valemetostat and each DXd ADC when administered in combination and determine the RDE
Part 2 Dose-expansion Phase: To evaluate investigator-assessed ORR, CR, and PR with valemetostat and each DXd ADC when administered in combination
Part 2 Dose-expansion Phase: To assess the safety and tolerability of valemetostat and T-DXd when administered in combination (Sub-protocol A)
Secondary Objectives
To evaluate OS with valemetostat and each DXd ADC when administered in combination
To evaluate PFS with valemetostat and each DXd ADC when administered in combination
To evaluate the DoR with valemetostat and each DXd ADC when administered in combination
Part 1 Dose-escalation Phase: To evaluate the efficacy of valemetostat and each DXd ADC when administered in combination
Part 2 Dose-expansion Phase: To assess the safety and tolerability of valemetostat and each DXd ADC when administered in combination (Sub-Protocols B and C)
To evaluate the PK of valemetostat and each DXd ADC when administered in combination
Inclusion Criteria
Sign and date the ICF prior to the start of any study-specific qualification procedures.
At least 18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
Has at least 1 measurable lesion based on investigator imaging assessment (computed tomography [CT] or magnetic resonance imaging [MRI] scans) using RECIST v 1.1 at Screening.
Is willing to provide an adequate tumor sample. This could include either undergoing a pre-treatment tumor biopsy procedure OR providing archival tissue sample (see Section 8.1).
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening (see Section 10.3.3).
Has adequate organ and bone marrow function within 14 days before the start of study drug. Transfusion (red blood cell or platelet) or granulocyte colony-stimulating factor (G-CSF) administration is not allowed within 14 days prior to the screening assessment. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days of the start of study drug as appropriate (Screening data may be used as Cycle 1 Day 1 if obtained within 72 hours prior to infusion). Adequate organ/bone marrow function is defined as follows: (See protocol)
If the subject is a female of childbearing potential, she must have a negative serum pregnancy test within 72 hours before the first dose of study drug and must be willing to use highly effective birth control, as detailed in Section 10.3.4. 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 or confirmed by follicle-stimulating hormone test (>40 mIU/mL) and estradiol (<40 pg/mL [<140 pmol/L]). Non-childbearing potential is defined as premenopausal females with a documented tubal ligation or hysterectomy, or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone >40 mIU/mL and estradiol <40 pg/mL [<147 pmol/L] is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the contraception methods outlined for female of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their postmenopausal status, they can resume use of HRT during the study without use of a contraceptive method.
If the subject is a male with a partner of childbearing potential, the subject must be surgically sterile or the subject and/or partner of childbearing potential must be willing to use highly effective birth control upon enrollment, during the Treatment Period, and for 4 months following the last dose of study drug. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period and at least 4 months after the final study drug administration.
Female subjects must not donate, or retrieve for their own use, ova from the time of Screening and throughout the Treatment Period and for at least 7 months after the final study drug administration.
Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
Exclusion Criteria
Has previously been treated with any EZH inhibitors.
Inadequate washout period prior to first dose, defined as follows: (See protocol)
Uncontrolled or significant cardiovascular disease, including the following:
a. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) >450 ms (males) or >470 ms (females; based on the average of Screening triplicate 12-lead electrocardiogram [ECG] determinations).
b. Myocardial infarction within 6 months prior to Screening.
c. Uncontrolled angina pectoris within 6 months prior to Screening.
d. New York Heart Association Class 2, 3, or 4 congestive heart failure (see Section 10.3.2).
e. LVEF <50% within 28 days before enrollment per echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
f. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg).
Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
Has leptomeningeal carcinomatosis or metastasis.
Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc), and any autoimmune, connective tissue, or inflammatory disorders with potential pulmonary involvement (ie, rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis, etc), or prior pneumonectomy (complete).
Current use of moderate or strong cytochrome P450 (CYP)3A inducers. For Part 1 Dose-escalation Phase only: Additionally, subjects with strong or moderate CYP3A inhibitors and P-glycoprotein (P-gp) inhibitors, unless these medications are discontinued at least 14 days prior to the study drug administration, will not be eligible (see Section 10.3.5).
Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (eg, prevention/treatment for transfusion reaction) or use for a noncancer indication (eg, adrenal replacement) is permissible.
History of another primary malignancy within the 3 years prior to enrollment, 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.
Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) v 5.0, Grade ≤1 or Baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to greater than Grade 2 for at least 3 months prior to enrollment and managed with SoC treatment), which the investigator deems related to previous anticancer therapy, composed of the following:
a. Chemotherapy-induced neuropathy
b. Fatigue
c. 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)
History of hypersensitivity to the drug substances or any excipients in the study drugs.
History of severe hypersensitivity reactions to other mAbs.
Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous (IV) antibiotics, antivirals, or antifungals. Note: Subjects with localized fungal infections of skin or nails are eligible.
Has any evidence of severe or uncontrolled systemic diseases, psychiatric illness/social situations, substance abuse, or other factors that in the investigator’s opinion make it undesirable for the subject to participate in the study or that would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
Has active human immunodeficiency virus (HIV) infection. Active HIV infection is determined by plasma HIV RNA viral load and cluster of differentiation 4 (CD4) count. Subjects with undetectable viral load and normalized CD4 count (CD4+ T cell counts ≥350 cells/μL) and no opportunistic infection within the past 12 months will be eligible. These subjects must be on established antiretroviral therapy for at least 4 weeks prior to enrollment. Subjects should be tested for HIV prior to enrollment if required by local regulations or Institutional Review Board (IRB)/Independent Ethics Committee. Note: Medications used for antiviral therapy should be reviewed for potential drug-drug interactions (see Exclusion criterion 8).
Has active hepatitis B or C infection. Active hepatitis C virus (HCV) is determined by anti-HCV antibody positive and detectable HCV RNA. Active hepatitis B virus (HBV) is determined by hepatitis B surface antigen (HBsAg) positive and/or detectable HBV DNA. Subjects positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Regarding hepatitis B, a subject is eligible if he or she:
a. Has received HBV vaccination with only anti-hepatitis B serological positivity and no clinical signs of hepatitis, hepatic cirrhosis/fibrosis, or HCV/HBV coinfection.
b. Is HBsAg negative and hepatitis B core (HBc) antibody positive (ie, those who have cleared HBV after infection) and meet the following criteria below:
HBV DNA viral load <2000 IU/mL.
Has normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection.
Starts or maintains antiviral treatment (for at least 4 weeks) if clinically indicated as per the investigator. Note: Medications used for antiviral therapy should be reviewed for potential drug-drug interactions (see Exclusion criterion 8).
Has a history of receiving live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose.
Female who is pregnant or breastfeeding or intends to become pregnant during the study. If the subject is a female who is willing to interrupt breastfeeding prior to enrollment, the subject must refrain from breastfeeding starting at Screening and throughout the study period and at least 7 months after the final study drug administration.
Psychological, social, familial, or geographical factors that would prevent regular follow-up.
