Trial Title:
A Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer
NCT ID:
NCT06503614
Condition:
Non-muscle Invasive Bladder Cancer
Non-Muscle Invasive Bladder Urothelial Carcinoma
Conditions: Official terms:
Urinary Bladder Neoplasms
Non-Muscle Invasive Bladder Neoplasms
Durvalumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
Durvalumab 1500mg IV
Arm group label:
Cohort A: Durvalumab and Monalizumab for CIS +/- high grade papillary urothelial cancer
Arm group label:
Cohort B: Durvalumab and Monalizumab for high grade papillary urothelial cancer without CIS
Other name:
MEDI 4736
Intervention type:
Drug
Intervention name:
Monalizumab
Description:
Monalizumab 1500mg IV
Arm group label:
Cohort A: Durvalumab and Monalizumab for CIS +/- high grade papillary urothelial cancer
Arm group label:
Cohort B: Durvalumab and Monalizumab for high grade papillary urothelial cancer without CIS
Summary:
This is a phase 2 open-label two cohort study of durvalumab plus monalizumab in patients
with BCG-unresponsive or exposed CIS NMIBC. Arm A will enroll 43 participants who have
cancer in situ (CIS) with or without high grade papillary urothelial cancer. Arm B will
enroll 17 participants who do not have cancer in situ (CIS) but do have high grade
papillary urothelial cancer. Eligible patients will be enrolled to receive up to 13
cycles of monthly combination of monalizumab and durvalumab. Both monalizumab and
durvalumab will be administered intravenously (IV) every 28 days.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age ≥18 years at the time of consent.
2. Patient is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations including
follow up. Able and willing to provide written informed consent.
3. Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.
4. Non-muscle-invasive bladder cancer
- Cohort A: CIS +/- high grade papillary urothelial cancer (Ta or T1)
- Cohort B: High grade papillary urothelial cancer (Ta or T1)
5. Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but
pure variant histology is ineligible. NOTE: Pathology report required for
documentation purposes.
6. Persistent disease (defined as not achieving disease free status) after completing
therapy with at least induction BCG (≥ 5 doses) and the first round of maintenance
or second induction course (≥ 2 doses). The subsequent round of BCG, either
maintenance or repeat induction, must be given within 6 months of initial induction
BCG.
- Persistent high risk NMIBC (T1, high grade papillary urothelial cancer Ta
and/or CIS) must be within 9 months of the last BCG instillation despite having
received adequate BCG as defined above.
7. High grade T1 after completing therapy with at least induction BCG (≥ 5 doses) or
after completing therapy with at least induction BCG (≥ 5 doses) and first round of
maintenance or second induction course (≥ 2 doses). The subsequent round of BCG,
either maintenance or repeat induction, must be given within 6 months of initial
induction BCG.
- Disease recurrence (T1) must be within 9 months of the last BCG instillation
despite having received adequate BCG as defined above.
8. Patients who are disease free at 6 months after starting BCG but have high grade
recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible.
- The recurrence must be within 6 months of the last BCG dose.
9. NMIBC patients, with high grade recurrence, having received adequate BCG within 24
months of last BCG exposure, are eligible.
10. Patients may have received up to 1 line of prior therapy (6 cycles of induction
chemotherapy) for NMIBC after BCG (NOTE: prior PD-1/PD-L1 blockade is prohibited).
11. Patients must be deemed unfit for radical cystectomy by the treating physician or
refuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should be
documented in the medical record.
12. All visible tumor must be completely resected within 60 days prior to registration
(residual pure CIS is permitted).
- All patients must have had a cystoscopy (or TURBT with complete resection)
without papillary tumor and negative urine cytology within 28 days prior to
registration (positive cytology is allowed in patients with CIS).
13. All patients with T1 tumors must undergo restaging TURBT within 60 days prior to
registration.
- There must be uninvolved muscularis propria in the restaging TURBT specimen.
- The initial TURBT prior to the restaging TURBT may be > 60 days prior to
registration.
14. Patients must have baseline tumor tissue from either initial or repeat TURBTs for
submission of a minimum of 2 and up to 10 unstained slides for translational study
objectives. If archival tissue is not available, the subject is not eligible.
15. Adequate organ function as defined by ALL of the following within 28 days prior to
registration:
- Absolute neutrophil count ≥ 1500/µL
- Platelets ≥ 100,000/µL
- Hemoglobin ≥ 9 g/dL
- Aspartate aminotransferase/alanine aminotransferase ≤ 1.5× upper limit of
normal (ULN)
- Total serum bilirubin ≤ 1.5×ULN*; *Patients with Gilbert's disease: ≤ 3×ULN
- International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) ≤ 1.5×ULN unless the patient is on therapeutic anticoagulation.
- Creatinine clearance ≥ 40 mL/min/1.73 m2 by Cockcroft-Gault estimation. The
patient's estimated CrCl will be calculated by the local laboratory (for
eligibility purposes) using screening/baseline height (m), actual weight (kg),
and serum creatinine:
Males: CrCl = ((140 - age in years) × weight (kg)) / (72× serum creatinine (mg/dL))
Females: CrCl = ((140 - age in years) × weight (kg) ×0.85) / (72× serum creatinine
(mg/dL))
16. Females of childbearing potential (FOCBP) must have a negative urine or serum
pregnancy test within 7 days of registration. If a urine test is done and it is
positive or cannot be confirmed as negative, a serum pregnancy test will be
required. FOCBP must agree to use contraception during the study.
17. Men capable of fathering a child must agree to use contraception during the study.
18. Must have a life expectancy of at least 12 weeks.
Exclusion Criteria:
1. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX
40, CD137).
2. Prior CIS of the ureters or prostatic urethra within 24 months prior to
registration.
3. Evidence of metastatic disease on imaging (CT or MRI) of the abdomen and pelvis
within 90 days of registration.
4. Body weight ≤ 30 kg.
5. History of allogeneic organ transplantation.
6. History of another primary malignancy other than muscle-invasive bladder cancer less
than 5 years prior to Day 1 of this trial, with the exception of a malignancy
treated with curative intent and with no known active disease ≥ 5 years before the
first dose of study drug and of low potential risk for recurrence. Other exceptions
include those with a negligible risk of metastasis or death and with expected
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal
or squamous cell skin cancer (non-melanoma skin cancer) or lentigo maligna without
evidence of disease, localized prostate cancer treated surgically with curative
intent, or ductal carcinoma in situ without evidence of disease treated surgically
with curative intent) or undergoing active surveillance per standard-of-care
management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with
Gleason score ≤ 6, and prostate specific antigen [PSA] ≤ 10 mg/mL, etc.)
7. Currently participating in or has participated in a trial of an investigational
agent within 4 weeks prior to the first dose of study treatment or 5 half-lives,
whichever is longer without recovery of clinically significant toxicities from that
therapy.
8. Active or prior autoimmune or inflammatory disorders requiring systemic treatment
within 24 months prior to registration. Autoimmune or inflammatory disorders
include, but not limited to, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease(colitis or Crohn's disease), diverticulitis (with the
exception of diverticulosis),antiphospholipid syndrome, Sarcoidosis syndrome, or
Wegener's syndrome (granulomatosis with polyangiitis, Graves' disease, hypophysitis,
uveitis, etc), Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple
sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. NOTE: The
following are exceptions to this criterion: Patients with vitiligo or alopecia,
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.
9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to registration. NOTE: Replacement
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment and is allowed.
10. Known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study.
11. Active tuberculosis.
12. Symptomatic herpes zoster within the past 30 days.
13. Active infection requiring systemic therapy. NOTE: Prophylactic antibiotics are
permitted. Treatment for a UTI is allowed but must be deemed adequately treated by
the treating physician prior the start of C1D1.
14. History of idiopathic pulmonary fibrosis or organizing pneumonia.
15. History of (non-infectious) pneumonitis that required steroids or have current
pneumonitis.
16. Patients known to have tested positive for human immunodeficiency virus (HIV)
(positive HIV 1/2 antibodies) are eligible with the following:
- On effective anti-retroviral therapy with undetectable viral load within 6
months of registration.
- HIV-infected participants must not have a history of Kaposi sarcoma and/or
Multicentric Castleman Disease.
17. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,
hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at
screening. Participants with a past or resolved HBV infection (defined as the
presence of anti HBc and absence of HBsAg) are eligible. Participants positive for
HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by a
local health authority.
18. Participants with a known co-infection with HBV and HCV, or co-infection with HBV
and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable
HBV DNA); AND HCV positive (presence of anti-HCV antibodies); OR HDV positive
(presence of anti-HDV antibodies).
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
20. Received live vaccines within 30 days of study treatment. Examples of live vaccines
include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccinations
are permitted.
21. Major surgical procedure (as defined by the Investigator) within 28 days prior to
the first dose of study drug. Note: Local surgery of isolated lesions for palliative
intent is acceptable.
22. Uncontrolled intercurrent illness, including but not limited to, symptomatic
congestive heart failure, uncontrolled hypertension, unstable angina pectoris,
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal
conditions associated with diarrhea, or psychiatric illness/social situations that
would limit compliance with study requirement, substantially increase risk of
incurring AEs or compromise the ability of the patient to give written informed
consent.
23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
24. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of study drug. See Section 5.5 for more
information.
25. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab may be included only after consultation with the
Study Physician.
26. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
27. History of leptomeningeal carcinomatosis
28. Prior randomization or treatment in a previous durvalumab clinical study regardless
of treatment arm assignment.
29. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
December 2024
Completion date:
December 2026
Lead sponsor:
Agency:
John Sfakianos
Agency class:
Other
Collaborator:
Agency:
AstraZeneca
Agency class:
Industry
Collaborator:
Agency:
Icahn School of Medicine at Mount Sinai
Agency class:
Other
Collaborator:
Agency:
Bladder Cancer Advocacy Network
Agency class:
Other
Source:
Hoosier Cancer Research Network
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06503614
