The standard first-line therapy for mUC patients is platinum-based chemotherapy, most commonly cisplatin. For patients that progress during or after platinum-based chemotherapy, anti-PD(L)1 therapy can be used, showing durable responses in a subset…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objective Response Rate (ORR) by investigator-assessed RECIST v1.1 by measuring
change in tumor burden. Patients will be evaluated after 12 weeks (=8 weeks
after introducing tremelimumab ± durvalumab) and then every 8 weeks for
RECIST1.1 response by CT-scan, for the first 12 months.
Secondary outcome
1) Establish safety of a combined schedule of paclitaxel, tremelimumab +/-
durvalumab in treatment of mUC patients. The safety evaluation will include
AEs, SAEs, and changes from baseline in laboratory evaluations, vital signs,
electrocardiograms, and physical examinations. The number and percentage of
subjects reporting treatment-emergent AEs will be summarized overall and by the
worst CTCAE grade, system organ class, and preferred term. Similarly, the
number and percentage of subjects reporting treatment-emergent AEs considered
related to investigational product will be summarized. At each level of subject
summarization, a subject will be counted once using the highest grade and level
of causality if one or more occurrences of the same system organ
class/preferred term are reported. Adverse events will be graded according to
the National Cancer Institute (NCI) CTCAE v5.0 and coded using the Medical
Dictionary for Regulatory Activities. Laboratory abnormalities will be graded
according to the NCI CTCAE v5.0, if applicable.
2) Determine clinical efficacy by additional measurements: OS and PFS by
Kaplan-Meier method, OS and PFS, Duration of response.
Background summary
Although a subset of patients show promising and durable responses to
anti-PD(L)1 treatment, the majority of mUC patients does not respond. Reasons
for failure to respond to anti-PD-(L)1 therapy could include insufficient
priming of the immune system by cancer antigens and/or negative regulation of
other steps in the *cancer immunity cycle*. Anti-CTLA4 treatment (tremelimumab)
could prevent negative regulation of T-cell priming and thereby broaden and
intensify the immune response to cancer antigens. For this process to occur,
presentation of cancer antigens is a prerequisite. Immune activation by
anti-CTLA4 could therefore likely be improved by combination with therapies
that induce tumor (neo-)antigen release. A relatively simple approach to
achieve this consists of providing an *immune-boost* using conventional
therapy. In addition to release of antigens and 'find-me' signals by apoptotic
cells, several lines of evidence support pro-immunogenic effects of
conventional chemotherapy, including taxanes. For example, paclitaxel decreased
accumulation and immunosuppressive activities of tumor-infiltrating MDSCs and
restored CD8 T cell effector functions, in a transgenic murine melanoma model.
Although response rates with taxanes are relatively low (10-15%) after
platinum-based therapy, a much higher percentage of patients achieves disease
control with limited (<30%) tumor shrinkage: 56% for the docetaxel/placebo arm
had disease control in the recently published RANGE trial, presumably involving
the induction of cancer cell death and (neo-) antigen release. Additionally,
platinum-refractory mUC is often characterized by rapid progression, which may
limit the chances of an immune response to occur. Taxane-induced disease
control, usually limited to approximately 2-6 months, may provide a sufficient
window for an immune response to occur. Combinations of taxanes with
immunotherapy, including with anti-CTLA4, have been clinically tested. One of
these studies combined carboplatin/paclitaxel with high-dose ipilimumab (10
mg/kg) in NSCLC. Toxicity was acceptable. This study used a concurrent schedule
and a *phased* schedule, in which ipilimumab was only added at cycle 3. The
latter schedule appeared more efficacious with respect to PFS and OS, though
this trial was designed to detect a difference between these arms
statistically. We will therefore introduce tremelimumab +/- durvalumab only
after 4 weeks in the current study. This schedule has the added advantage that
immunotherapy is not introduced concurrently with steroids, which are usually
given for the first two administrations of taxanes to prevent infusion reaction
(day 1,8 in a weekly paclitaxel schedule). In conclusion, paclitaxel, followed
by tremelimumab monotherapy or tremelimumab in combination with durvalumab, may
still induce responses in advanced mUC patients who have previously been
treated with chemotherapy and immunotherapy by influencing the tumor
micro-environment.
Study objective
The standard first-line therapy for mUC patients is platinum-based
chemotherapy, most commonly cisplatin. For patients that progress during or
after platinum-based chemotherapy, anti-PD(L)1 therapy can be used, showing
durable responses in a subset of patients. However, the majority of patients do
not respond to anti-PD(L)1 therapy, Second-line chemotherapeutics, like
vinflunine and taxanes, have very limited OS and PFS benefits. There is
therefore a high clinical need for new treatment strategies for this subgroup
of patients. We hypothesize that, by combining additional immune checkpoint
inhibitors with paclitaxel, we will be able to induce a more immune-susceptible
tumor micro-environment, which will lead to an increase of infiltrating immune
cells and improved efficacy of immune checkpoint inhibition. We will
specifically target mUC patients that have received previous anti-PD(L)1
therapy and chemotherapy (or patients who were ineligible to receive
cisplatin). By combining paclitaxel with either high-dose anti-CTLA4
monotherapy every four weeks or with a single dose of anti-CTLA4 combined with
anti-PDL1every four weeks, we hope to induce (durable) responses in this
difficult-to-treat patient group.
Study design
This study is a multi-center, randomised trial consisting of 2 phases with a
total number of patients of N=53. During the 'run-in-safety' phase (1b) we will
investigate if patients tolerate paclitaxel combined with either a high dose of
tremelimumab or otherwise a single regular dose of tremelimumab combined with
durvalumab. During the experimental phase (2) we will investigate the efficacy
in both treatment arms.
Intervention
Run-in phase-1 (R1): n=3 patients will be treated with:
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 75 mg on day 1 of cycles 2-6 and then every 12 weeks until week
45
Run-in phase-2 (R2): n=3 patients will be treated with:
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 225 mg on day 1 of cycles 2-6 and then every 12 weeks until week
45
Run-in phase-3 (R3): n=2 x 3 patients will be randomized over 2 arms (R3A and
R3B):
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week
45
OR
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 75 mg on day 1 of cycles 2-5
• durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Run-in phase-4 (R4): n=3 patients will be treated with:
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 300 mg once on day 1 of cycle 2
• durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
patients in R3A and R4 will be included in arm A and B respectively
Main study:
Arm A:
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 750 mg on day 1 of cycles 2-6 and then every 12 weeks until week
45
Arm B:
• paclitaxel 70 mg/m2 on day 1, 8, 15 of cycles 1-6
• tremelimumab 300 mg once on day 1 of cycle 2
• durvalumab 1500 mg on day 1 of cycles 2-12, every four weeks (until week 49)
Arm C (control arm):
• tremelimumab 750 mg on day 1 of cycles 1-5 and then every 12 weeks until week
41
The experimental arm that shows the best responses will be extended to n=20
Study burden and risks
During the first 12 months after inclusion, patients will regularly visit the
hospital for check-ups and drug administration. On average 25 visits will be
planned. During each visit, blood will be drawn to monitor response to therapy
and CT-scans will be made once every 8 weeks to monitor tumor response.
Patients have a chance to experience side-effects due to immunotherapy or
chenmtherapy effects. Furthermore, there is a chance of infusion-related events
or side-effects due to the biopsies or blood withdrawal.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:, 1.
Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in
this protocol. Written informed consent and any locally required authorization
(eg, European Union [EU] Data Privacy Directive) obtained from the
patient/legal representative prior to performing any protocol-related
procedures, including screening evaluations. , 2. Patients with histologically
or cytologically documented metastatic or irresectable (i.e. T4b, N1-3 and/or
M1a/b) urothelial cell carcinoma (including renal pelvis, ureters, urinary
bladder, and urethra)., 3. Patients ineligible for cisplatin-based chemotherapy
OR previous treatment with platinum-based chemotherapy, either in the
neo-adjuvant setting or in any other setting. This is defined as progression on
or after at least 2 cycles of platinum-based chemotherapy (e.g. MVAC,
cisplatin/gemcitabine, carpoblatin/gemcitabine). Patients who had to stop
platinum-based therapy because of toxicity after at least 2 cycles are eligible
if they have progressive disease. , 4. Previous treatment with anti-PD(L)1
immunotherapy. The following conditions apply for inclusion:, a. Must not have
experienced a toxicity that led to permanent discontinuation of prior
anti-PD(L)1 immunotherapy. , b. All treatment-related AEs while receiving prior
anti-PD(L)1 immunotherapy must have completely resolved or resolved to baseline
prior to screening for this study., c. Must not have experienced a >=Grade 3
immune related AE or an immune related neurologic or ocular AE of any grade
while receiving prior anti-PD(L)1 immunotherapy. , d. Patients with endocrine
AE of <=Grade 2 are permitted to enroll if they are stably maintained on
appropriate replacement therapy and are asymptomatic., e. Must not have
required the use of additional immunosuppression other than corticosteroids for
the management of an AE, not have experienced recurrence of an AE if
re-challenged, and not currently require maintenance doses of >10 mg prednisone
or equivalent per day., 5. At least 1 lesion, not previously irradiated, that
can be accurately measured at baseline as >=10 mm in the longest diameter
(except lymph nodes which must have a Revised Clinical Study Protocol short
axis >=15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI)
and that is suitable for accurate repeated measurements as per Response
Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines., 6.
Age >18 years at time of study entry, 7. World Health Organisation (WHO)
performance status of 0 or 1, 8. Body weight >30kg , 9. Adequate normal organ
and marrow function as defined below: , a. Haemoglobin >=9.0 g/dL = 5.6 mmol/L,
b. Absolute neutrophil count (ANC) >=1.5 x 109/L, c. Platelet count >=100 x
109/L, d. Serum bilirubin <=1.5 x institutional upper limit of normal (ULN).
(Does not apply to patients with confirmed Gilbert*s syndrome, who will be
allowed only in consultation with their physician.), e. AST (SGOT)/ALT (SGPT)
<=2.5 x institutional upper limit of normal unless liver metastases are present,
in which case it must be <=5x ULN, f. Measured creatinine clearance (CL) >30
mL/min or Calculated creatinine clearance CL>30 mL/min by the Cockcroft-Gault
formula (Cockcroft and Gault 1976) or by 24-hour urine collection for
determination of creatinine clearance:, Males: , Creatinine CL (mL/min) =
Weight (kg) x (140 - Age) , 72 x serum creatinine (mg/dL), Females: ,
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85, 72 x serum
creatinine (mg/dL), 10. Evidence of post-menopausal status or negative urinary
or serum pregnancy test for female pre-menopausal patients. Women will be
considered post-menopausal if they have been amenorrheic for 12 months without
an alternative medical cause. The following age-specific requirements apply:, •
Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating
hormone levels in the post-menopausal range for the institution or underwent
surgical sterilization (bilateral oophorectomy or hysterectomy)., • Women >=50
years of age would be considered post-menopausal if they have been amenorrheic
for 12 months or more following cessation of all exogenous hormonal treatments,
had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy)., 11. 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., 12. Must have a life expectancy of at
least 12 weeks
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and/or staff at the study site), 2. Participation in another
clinical study with an investigational product , 3. Concurrent enrollment in
another clinical study, unless it is an observational study, 4. Receipt of the
last dose of anticancer therapy <=28 days prior to the first dose of study
drug., 5. 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 , 6. Any concurrent chemotherapy,
investigational product (IP), biologic, or hormonal therapy for cancer
treatment. , 7. Radiotherapy treatment to more than 30% of the bone marrow or
with a wide field of radiation within 4 weeks of the first dose of study drug,
8. Major surgical procedure within 28 days prior to the first dose of IP. , 9.
History of allogenic organ transplantation., 10. Active or prior documented
autoimmune or inflammatory disorders , 11. Uncontrolled intercurrent illness,
including but not limited to, ongoing or active infection, 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, 12. History of another primary malignancy except for, •
Malignancy treated with curative intent and with no known active disease >=2
years before the first dose of IP and of low potential risk for recurrence, •
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease, • Adequately treated carcinoma in situ without evidence of disease,
• Curatively treated localized prostate cancer without PSA recurrence, 13.
History of leptomeningeal carcinomatosis, 14. Brain metastases or spinal cord
compression, unless they show radiographic stability, 15. History of active
primary immunodeficiency , 16. Active infection including tuberculosis
(clinical evaluation that includes clinical history, physical examination and
radiographic findings), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2
antibodies). Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA., 17. Current or prior use of
immunosuppressive medication within 14 days before the first dose of durvalumab
or tremelimumab. 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), 18. Receipt of live
attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and
up to 30 days after the last dose of IP., 19. 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 180 days after
the last dose of tremelimumab, durvalumab, or durvalumab + tremelimumab
combination therapy., 20. Known allergy or hypersensitivity to any of the study
drugs or any of the study drug excipients., 21. Prior randomisation or
treatment in a previous durvalumab and/or tremelimumab clinical study
regardless of treatment arm assignment. , 22. Previous treatment with
anti-CTLA-4 immunotherapy., 23. Known allergy or hypersensitivity to IP or any
excipient
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004148-53-NL |
| CCMO | NL67737.031.18 |