Phase II Trial of Ubamatamab Alone or in Combination with Cemiplimab in MUC16-Expressing SMARCB1-Deficient Malignancies

Last updated: January 13, 2025
Sponsor: M.D. Anderson Cancer Center
Overall Status: Active - Recruiting

Phase

2

Condition

Neoplasms

Treatment

Cemiplimab

Ubamatamab

Clinical Study ID

NCT06444880
2023-1062
NCI-2024-04755
  • Ages > 12
  • All Genders

Study Summary

To find out if ubamatamab, given by itself or in combination with cemiplimab, can help to control the disease in participants with renal medullary carcinoma (RMC) and epithelioid sarcoma (ES).

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Participants with locally advanced or metastatic RMC (RMC cohort) or ES (ES cohort)histologically confirmed by expert pathology review and loss of SMARCB1 staining byIHC. Participants with advanced or metastatic unclassified renal cell carcinoma withmedullary phenotype (a rare SMARCB1 negative RMC variant occurring in individualswithout sickle hemoglobinopathies) are also eligible for the RMC cohort.

  2. Eligible participants should either demonstrate serum CA-125 levels ≥ 70 units/mlduring screening or positive H score of >25 for MUC16 (CA-125) by IHC in tumortissues collected within 12 months from screening as noted in participant EMR:

  3. The H score is calculated using the standard formula commonly used in IHC: Hscore = [(0 x % negative cells) + (1 x % weak positive cells) + (2 x % moderatepositive cells) + (3 x % strong positive cells). For instance, if 50% of tumorcells show weak staining, 30% of tumor cells show moderate staining, and 20% ofcells show strong staining, the H-score would be: (50×1)+(30×2)+(20×3)=50+60+60=170.

  4. If serum CA-125 ≥ 70 units/ml then participants will be enrolled without delay.IHC for MUC16 will be used as a correlative biomarker but not for trialeligibility.

  5. If serum CA-125 < 70 units/ml then for trial eligibility, MUC16 expressionshould be checked by IHC in tumor tissues collected within 12 months fromscreening: i. If H score is < 25 then the patient will not be eligible for the trial ii. If Hscore ≥ 25 then the patient will be eligible for the trial

  6. Participants will be eligible in the RMC cohort regardless of whether they have hadprior nephrectomy or still have their primary tumor in-situ.

  7. Participants must have at least one measurable site of disease, defined as a lesionthat can be accurately measured in at least one dimension (longest diameter to berecorded) and measures ≥ 15 mm with conventional techniques or ≥ 10 mm with moresensitive techniques such as MRI or CT scan. If the patient has had previousradiation to the marker lesion(s), there must be evidence of progression since theradiation.

  8. Participants must have progressed on at least one line of prior therapy.

  9. There must be evidence of progression on or after last treatment regimen received.

  10. ECOG performance status 0-1 a. NOTE: If participant is unable to walk due to paralysis, but is mobile in awheelchair, participant is considered to be ambulatory for the purpose of assessingtheir performance status.

  11. Age (at the time of consent/assent): ≥ 18 years a. RMC is the third most common renal cell carcinoma in children and young adults inthe United States21 and while we will initially enroll participants aged ≥18 yearsold, we will in coordination with Regeneron consider allowing pediatric participants ≥12 years old if no trial limiting toxicities (TOX), as defined in Section 9.1.2.,after the interim analysis of the first 10 participants enrolled and based on theaccumulated pharmacokinetic / pharmacodynamic data of ubamatamab in this populationat that time. If these criteria are fulfilled, then adolescent participants age 12years and older will be allowed with signed assent and parental consent according toinstitutional guidelines and requirements, as long as their weight is >40 kg giventhat this is the lower weight limit for which safety following ubamatamab with orwithout cemiplimab exposure has been ascertained.

  12. Consent to MD Anderson companion laboratory protocol 2014-0938

  13. Participants must have adequate organ and marrow function as defined below: Hemoglobina ≥ 9 g/dl (treatment allowed) Absolute neutrophil countb ≥ 1,000/µLPlatelets ≥ 75,000/µL Total bilirubin ≤ 1.5 mg/dl AST(SGOT) or ALT (SGPT) ≤ 2.5 Xinstitutional ULN, except in known hepatic metastasis, wherein may be ≤ 5 x ULNSerum Creatininec ≤ 1.5 x ULN by gender (as long as patient does not requiredialysis) a May receive transfusion within the screening period b Without growth factorsupport (filgrastim or pegfilgrastim) for at least 14 days c If creatinine is not <1.5×ULN, then calculate by Cockcroft-Gault methods or local institutional standardand CrCl must be >30 mL/kg/1.73 m2

  14. Participants with controlled brain metastases are allowed on protocol if the brainmetastases were surgically resected or treated with radiosurgery or Gamma knife,without recurrence or edema for 1 month (4 weeks). Participants actively requiringglucocorticoids for uncontrolled brain or leptomeningeal metastases are noteligible.

  15. Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24hours prior to the start of the study drug.

  16. Women must not be breastfeeding.

  17. WOCBP must agree to follow instructions for method(s) of contraception from the timeof registration for treatment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for atotal of 5 months post treatment completion. Men must agree to effectivecontraception from the time of registration for treatment to 7 months post lastprotocol treatment. Investigators shall counsel WOCBP and male participants who are sexually active withWOCBP on the importance of pregnancy prevention and the implications of anunexpected pregnancy Investigators shall advise WOCBP and male participants who aresexually active with WOCBP on the use of highly effective methods of contraception.Highly effective methods of contraception have a failure rate of < 1% per year whenused consistently and correctly. Approved methods of birth control are as follows: Hormonal contraception (i.e. birthcontrol pills, injection, implant, transdermal patch, vaginal ring), Intrauterinedevice (IUD), Tubal Ligation or hysterectomy, Patient/Partner post vasectomy,Implantable or injectable contraceptives, and condoms plus spermicide. Not engagingin sexual activity for the total duration of the trial and the drug washout periodis an acceptable practice; however periodic abstinence, the rhythm method, and thewithdrawal method are not acceptable methods of birth control. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 7months after completion of ubamatamab/cemiplimab administration. The effects of ubamatamab/cemiplimab on the developing human fetus are unknown. Forthis reason and because immunotherapy agents as well as other therapeutic agentsused in this trial are known to be teratogenic, women of child-bearing potential andmen must agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry and for the duration of studyparticipation. (Refer to Pregnancy Assessment Policy MD Anderson InstitutionalPolicy # CLN1114). This includes all female participants, between the onset ofmenses (as early as 8 years of age) and 55 years unless the patient presents with anapplicable exclusionary factor which may be one of the following:

  • Postmenopausal (no menses in greater than or equal to 12 consecutive months).

  • History of hysterectomy or bilateral salpingo-oophorectomy.

  • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausalrange, who have received Whole Pelvic Radiation Therapy).

  • History of bilateral tubal ligation or another surgical sterilizationprocedure.

  1. Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion

Exclusion Criteria:

  1. Participants must not have any other malignancies within the past 2 years except forin situ carcinoma of any site, or adequately treated (without recurrencepost-resection or post-radiotherapy) carcinoma of the cervix or basal or squamouscell carcinomas of the skin, ductal carcinoma in situ of the breast or low-riskearly stage prostate adenocarcinoma with negligible risk of metastasis or death

  2. Participants previously treated with T-cell-redirecting bispecific antibodies orMUC16-targeted therapies (including vaccines) are excluded. Participants whoreceived CAR-T therapies within 30 days of first dose of study drug are alsoexcluded. However, participants previously treated with immune checkpoint therapiessuch as anti-PD1, anti-PD-L1, anti-CTLA-4, or anti-LAG-3 immune checkpointinhibitors are eligible, as long as they have been off these therapies for at least 60 days (~3 half-lives) prior to initiation of study treatment with ubamatamab.

  3. Participants currently receiving anticancer therapies or who have receivedanticancer therapies (including chemotherapy and targeted therapies such astazemetostat) within 2 weeks (14 days) prior to study Day 1 are excluded.Participants who have completed palliative radiation therapy more than 14 days priorto the first dose of the combination immunotherapy are eligible.

  4. Participants with persistent grade ≥2 adverse events from prior systemic therapiesthat would confound timely detection of immune-related adverse events due toubamatamab and/or cemiplimab or otherwise hinder patient participation in theclinical trial.

  5. Participants, who have had a major surgery or significant traumatic injury (injuryrequiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of studydrug, participants who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia).

  6. Participants who have organ allografts.

  7. Known or suspected autoimmune disease. Participants with a history of inflammatorybowel disease (including Crohn's disease and ulcerative colitis) and autoimmunedisorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g.,Wegener's Granulomatosis] are excluded from this study. Participants with a historyof Hashimoto's thyroiditis only requiring hormone replacement, Type I diabetes, orpsoriasis not requiring systemic treatment, or conditions not expected to recur inthe absence of an external trigger are allowed to participate.

  8. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis Cinfection; or diagnosis of immunodeficiency.

  9. Participants with HIV who have controlled infection (undetectable viral loadwith the exception of clinically insignificant blips and CD4 count above 350either spontaneously or on a stable antiviral regimen) are permitted.

  10. Participants with hepatitis B surface antigen positive (HepBsAg+) who havecontrolled infection (serum hepatitis B virus DNA PCR that is below the limitof detection AND receiving antiviral therapy for hepatitis B) are permitted.

  11. Participants with HBsAg negative but total HBV core antibody positive (HBc Ab+)are permitted with the following requirements: Serum HBV DNA PCR should betested and if it is above the limit of detection at screening then antiviraltherapy for HBV must be initiated prior to study entry. If serum HBV DNA PCR isbelow the limit of detection periodic monitoring of HBsAg must be performedevery 12 months +/- 3 months.

  12. Participants who are Hepatitis C virus antibody positive (HCV Ab +) who havecontrolled infection (undetectable HCV RNA by PCR either spontaneously or inresponse to a successful prior course of anti-HCV therapy) are permitted.

  13. Any underlying medical condition, which in the opinion of the Investigator, willmake the administration of study drug hazardous or obscure the interpretation ofadverse events, such as a condition associated with frequent diarrhea, uncontrollednausea or vomiting. Patients with active COVID-19 disease as indicated by a positivepolymerase reaction (PCR) test are excluded. Participants with previous COVID-19disease are allowed if ≥30 days from last positive test, and COVID-19 symptoms haveresolved and/or PCR test is now negative.

  14. Participants must not be scheduled to receive another experimental drug while onthis study.

  15. Participants who are on high dose steroid (e.g., > 10mg prednisone daily orequivalent) or other more potent immune suppression medications (e.g., infliximab).Topical, inhaled, intra-articular, ocular, or intranasal corticosteroids (withminimal systemic absorption) are allowed. A brief course (<48 hours) of systemiccorticosteroids for prophylaxis (eg, from contrast dye allergy) is permitted.Physiological corticosteroid replacement therapy for adrenal insufficiency (up tohydrocortisone 30 mg / daily or equivalent) is also permitted.

  16. Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% bytransthoracic echocardiogram (TTE) within 6 months prior to start of studytreatment. In cases of LVEF 45-50% in absence of clinical symptoms, after review andclearance by cardiologist, the patient may be enrolled.

  17. Active myocarditis, regardless of etiology.

  18. Moderate to large pericardial effusion (eg, > approximately 100 mL) as measured byechocardiogram at baseline. Multigated acquisition (MUGA) is not sufficient forevaluating pericardial effusion.

  19. Has a history of any clinically significant arrhythmia including atrial fibrillationor implantation of a pacemaker or defibrillator.

  20. Participants who have any severe and/or uncontrolled medical conditions or otherconditions that could affect their participation in the study such as:

  21. Symptomatic congestive heart failure of New York heart Association Class III orIV

  22. Unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction within 6 months of start of study drug, serious uncontrolled cardiacarrhythmia or any other clinically significant cardiac disease

  23. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection andwithout improvement) despite appropriate antibiotics or other treatment.

  24. Participants with a history of major psychiatric illness judged unable to fullyunderstand the investigational nature of the study and the risks associatedwith the therapy.

  25. Participants must not have history of other diseases, metabolic dysfunction,physical examination finding, or clinical laboratory finding giving reasonablesuspicion of a disease or condition that contraindicates the use of ubamatamab orcemiplimab or that might affect the interpretation of the results of the study orrender the participant at high risk from treatment complications.

  26. Participants should not receive immunization with attenuated live vaccines within 30days of planned start of study medication. a. Note: Seasonal influenza vaccines for injection are generally inactivated fluvaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®)are live attenuated vaccines, and are not allowed.

  27. Female participants who are pregnant or breast feeding, or adults of reproductivepotential who are not willing to use effective birth control methods as definedabove.

  28. Any participants who cannot be compliant with the appointments required in thisprotocol must not be enrolled in this study.

  29. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ubamatamab or cemiplimab.

  30. Participants with psychiatric illness/social situations that would limit compliancewith study requirements.

Study Design

Total Participants: 40
Treatment Group(s): 2
Primary Treatment: Cemiplimab
Phase: 2
Study Start date:
October 09, 2024
Estimated Completion Date:
July 31, 2028

Study Description

Primary Objectives • To determine the objective response rate (ORR) and disease control rate (DCR), per RECIST 1.1, of ubamatamab alone and in combination with cemiplimab in patients with locally advanced or metastatic MUC16-expressing SMARCB1-deficient malignancies, RMC or ES, who have progressed on at least one prior line of therapy.

Secondary Objectives

• To determine the efficacy and safety of ubamatamab alone or in combination with cemiplimab in participants with locally advanced or metastatic MUC16-expressing SMARCB1-deficient malignancies such as RMC or ES who have progressed on at least one prior line of therapy. Efficacy will be measured by overall survival (OS), progression-free survival (PFS), and duration of response (DOR).

Exploratory Objectives

  • To determine the objective response rate (ORR) and disease control rate (DCR), per RECIST 1.1, of the overall strategy of ubamatamab alone followed by combination with cemiplimab in participants with locally advanced or metastatic MUC16-expressing SMARCB1-deficient malignancies, RMC or ES, who have progressed on at least one prior line of therapy.

  • To evaluate potential biomarkers, such as serum CA-125 and tumor tissue MUC16 expression levels for participant stratification, and to determine via the molecular profiling of biopsy and blood specimens, the mechanisms of resistance to ubamatamab alone or in combination with cemiplimab.

Connect with a study center

  • MD Anderson Cancer Center

    Houston, Texas 77030
    United States

    Active - Recruiting

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