ObjectivesPrimary* To determine the efficacy (as assessed by radiographic progression free survival [rPFS]) of AZD4635 plus durvalumab and separately of AZD4635 plus durvalumab plus cabazitaxel in participants with mCRPC.Secondary* To evaluate the…
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Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is rPFS defined as the time from first dose until
radiographic progression as assessed by the Investigator per RECIST v1.1 (soft
tissue) and PCWG3 (bone) or death from any cause, whichever comes first.
Radiological progression-free survival (rPFS)
Progression-free survival is defined as the time interval from the first dose
of AZD4635 until the date of objective disease progression or death (by any
cause in the absence of progression) regardless of whether the participant
withdraws from treatment or receives another anti-cancer therapy prior to
progression. Participants who have not progressed (defined as CR, PR or SD by
RECIST v1.1 for soft tissue disease, or non-PD for bone disease) at the time of
analysis will be censored at the time of the last evaluable RECIST v1.1
assessment or bone scan.
However, if the participant progresses or dies after 2 or more missed
radiologic visits the participant will be censored at the time of the last
evaluable RECIST v1.1 or bone scan assessment prior to the 2 missed visits. If
a participant has an assessment for soft tissue disease (MRI/CT) but not for
bone disease (bone scan), or vice versa, then this will count as a missed
assessment. If the participant has no evaluable post-baseline RECIST v1.1 or
bone scan assessments they will be censored at Day 1 unless they die within 2
visits of baseline (in which case their date of death will be used).
Progression-free survival will be derived based on scan/assessment dates not
the scheduled visit dates. If RECIST v1.1 assessments/bone scans contributing
toward a particular visit are performed on different dates then the date of
progression will be determined based on the earliest of the dates of the
component that triggered the progression. With regard to censoring, a
participant will be censored at the latest of the dates contributing to a
particular overall visit assessment. Summaries (number of events, medians,
proportion and 95% CI for progression free at fixed time points using the
Kaplan-Meier estimate) and Kaplan-Meier plots will be provided. A 2-sided 95 %
CI for the median PFS will be produced in addition to the 25th and 75th
percentiles.
Secondary outcome
Secondary endpoints include: safety, OS, ORR, DoR, PSA50 response, time to pain
progression, and PK. The analysis will be descriptive and summaries will be
presented for each arm. Relevant efficacy endpoints will also be summarised for
biomarker high and low subgroups.
Secondary endpoints
* Physical examination, laboratory values (haematology, clinical chemistry,
urinalysis, and tests for coagulation), vital signs, and electrocardiograms
(ECGs).
* Adverse events/serious adverse events (AEs/SAEs) collected throughout the
study, from the time of the informed consent form signature through to the last
safety follow-up visit.
* OS, defined as the time from first dose until death due to any cause
regardless of whether the participant withdraws from study treatment or
receives another anti-cancer therapy.
* Confirmed ORR, defined as the percentage of participants with a confirmed
Investigator-assessed response of CR or PR using overall radiographic response
assessed by RECIST v1.1 and PCWG-3 criteria (bone), and will be based on a
subset of all treated participants with measurable disease at baseline per the
site Investigator.
* DoR, defined as the date of first documented response (which is subsequently
confirmed) until the date of documented progression or death in the absence of
disease progression.
* Confirmed PSA50 response, defined as the proportion of participants achieving
a *50% decrease in PSA from baseline to the lowest post-baseline PSA, confirmed
by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable
participants (dosed participants with an abnormal baseline PSA [*1 ng/mL]).
* AZD4635, durvalumab and cabazitaxel plasma concentrations and derived PK
parameters, where deemed appropriate.
* rPFS, defined as the time from first dose until radiographic progression,
assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria
(bone) or death from any cause, whichever occurs first by gene expression
subgroup.
* OS, defined as the time from first dose until death due to any cause
regardless of whether the participant withdraws from study treatment or
receives another anti-cancer therapy.
* Confirmed objective response rate (ORR), defined as the percentage of
participants with a confirmed Investigator-assessed response of CR or PR using
overall radiographic response assessed by RECIST v1.1 and PCWG-3 criteria
(bone), and will be based on a subset of all treated participants with
measurable disease at baseline per the site Investigator. Duration of response
(DoR), defined as the date of first documented response (which is subsequently
confirmed) until the date of documented progression or death in the absence of
disease progression.
* Confirmed PSA50 response, defined as the proportion of participants
achieving a *50% decrease in PSA from baseline to the lowest post-baseline PSA,
confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA
evaluable participants (dosed participants with an abnormal baseline PSA [*1
ng/mL]).
* Time to pain progression based on Brief Pain Inventory (Short Form) (BPI SF)
Item 3 *pain at its worst in the last 24 hours*.
* rPFS, defined as the time from first dose until radiographic progression,
assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria
(bone) or death from any cause, whichever occurs first by gene expression
subgroup.
* OS, defined as the time from first dose until death due to any cause
regardless of whether the participant withdraws from study treatment or
receives another anti-cancer therapy.
* Confirmed objective response rate (ORR), defined as the percentage of
participants with a confirmed Investigator-assessed response of CR or PR using
overall radiographic response assessed by RECIST v1.1 and PCWG-3 criteria
(bone), and will be based on a subset of all treated participants with
measurable disease at baseline per the site Investigator.
* Duration of response (DoR), defined as the date of first documented response
(which is subsequently confirmed) until the date of documented progression or
death in the absence of disease progression.
* Confirmed PSA50 response, defined as the proportion of participants
achieving a *50% decrease in PSA from baseline to the lowest post-baseline PSA,
confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA
evaluable participants (dosed participants with an abnormal baseline PSA [*1
ng/mL]).
* Time to pain progression based on BPI SF Item 3 *pain at its worst in the
last 24 hours*.
* Change from baseline in worst pain, average pain and pain interference in the
daily activities scales of the BPI-SF.
* Time to pain progression based on BPI SF Item 3 *pain at its worst in the
last 24 hours *.
* Change from baseline in the FAPSI 6 as derived from 6 items, the FAPSI-8 as
derived from 8 items within the FACT P, and the PCS as derived from the 12
items in the prostrate-specific module of the FACT P.
Exploratory
* iRECIST.
The results of this exploratory biomarker research will not form part of the
CSR.
* Exploratory endpoints will include but are not limited to genomic status,
including gene expression, whole blood and serum analytes, and biopsies where
possible. This may include collection of genomic status including gene
expression, whole blood and serum analytes from previous samples, if available.
Their association with efficacy endpoints will be explored. Features of immune
status such as T cell receptor repertoire, expression of immune-related genes,
tumour mutational burden and microsatellite instability (MSI) status will be
explored.
The results of this exploratory biomarker research will not form part of the
CSR.
* Correlation of polymorphisms with variations in safety or response parameters
to study interventions.
The results of this exploratory biomarker research will not form part of the
CSR.
* Collection of plasma samples to include, but not be limited to extraction of
ctDNA for investigation of blood-borne cancer biomarkers. Correlate ctDNA
longitudinal kinetics with patterns of response and relapse.
The results of this exploratory biomarker research will not form part of the
CSR.
* Collection of samples to include but, not be limited to, whole blood, plasma,
and tissue samples (tumour, bone, or lymph node biopsies). Measured methods
including, but not be limited to gene and protein expression, DNA
amplification, and enzymatic activity.
The results of this exploratory biomarker research will not form part of the
CSR.
Background summary
Prostate cancer is the second most common cancer in men. In 2018, over 1.2
million new cases of prostate cancer were diagnosed worldwide and there were
350,000 deaths due to the disease (Bray et al. 2018). For men requiring
systemic therapy, hormonal therapy has been the mainstay. Once the disease
becomes resistant to hormonal therapy, the disease is known as
castration-resistant prostate cancer (CRPC). Treatment for both metastatic and
non-metastatic prostate cancer has evolved over the past 15 years. In 2004, the
development of a docetaxel regimen for the treatment of CRPC was the first
chemotherapy to show a survival benefit and subsequently became the
standard-of-care chemotherapy for CRPC. A regimen of docetaxel given Q3W had a
median OS of 18.9 months (95% CI 1417.0-21.2), which was greater than the
survival of 16.5 months (95% CI 14.4 * 18.6 months) for a mitoxantrone control
arm. The hazard ratio (HR) for death was 0.76 (95% CI 0.62-0.94, p=0.009) for
docetaxel compared to mitoxantrone (Tannock et al. 2014). However, many of the
treatments for prostate cancer, including docetaxel and cabazitaxel for mCRPC,
are not suitable for all patients and many patients are refractory to these
treatments so alternative treatment options are needed.
New hormonal agents have become standard of care for mCRPC and include
enzalutamide and abiraterone plus prednisone. Enzalutamide, a targeted
androgen-receptor inhibitor that blocks the binding of androgen to the androgen
receptor, translocation to the nucleus, and DNA binding (Tran et al. 2009), was
approved for the first-line treatment of patients with mCRPC. Abiraterone, a
selective inhibitor of 17 *-hydroxylase/C17,20-lyase (CYP17), was also approved
in combination with prednisone for the treatment of mCRPC in the first-line
setting (Ryan et al. 2013a, Ryan et al. 2013b).
AZD4635 is being developed as monotherapy and as an immuno-oncology agent in
combination with durvalumab (anti-PD-L1) and durvalumab plus oleclumab (cluster
of differentiation 73 [CD73] monoclonal antibody), exploiting complementary
immune-related mechanisms to broaden and deepen clinical responses. AZD4635 has
shown activity in a variety of tumour types, with encouraging data being seen
for the combination AZD4635 and durvalumab in the Phase I study. As stated
previously, this Phase II study will evaluate the efficacy, safety and
tolerability of the combination of AZD4635 and durvalumab and the combination
of AZD4635 with durvalumab and cabazitaxel. In addition, the study will explore
the combination of AZD4635 plus durvalumab in a selected participant population
using a biomarker-derived signature shown to correlate with participant
outcomes (Sidders et al., recently accepted by Clinical Cancer Research.)
Durvalumab (IMFINZI®) is FDA-approved in patients with bladder urothelial
carcinoma who have disease progression during or following platinum containing
chemotherapy and in patients who have disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum containing chemotherapy.
Durvalumab is also approved in patients with NSCLC whose disease has not
progressed following concurrent platinum based chemotherapy and radiation
therapy. Durvalumab, in combination with etoposide and either carboplatin or
cisplatin, is also approved for the first-line treatment of adult patients with
extensive-stage small cell lung cancer (ES-SCLC) (IMFINZI® US Prescribing
Information).
Durvalumab is approved by the European Medicines Agency (EMA) as monotherapy
for the treatment of locally advanced, unresectable NSCLC in adults whose
tumours express PD-L1 on *1% of tumour cells and whose disease has not
progressed following platinum-based chemo-radiation therapy (IMFINZI®, EU SmPC).
Although NHAs have changed the landscape of treatment for mCRPC, for patients
who have progressed on NHAs and docetaxel, there remain limited therapeutic
options. While immunotherapy has led to impressive responses in a subset of
patients with immunologically *activated* tumours, this approach has shown
little progress in mCRPC. The addition of AZD4635 to anti-PD/PDL1 therapy or
the combination of anti-PDL1 plus cabazitaxel may lead to an improvement in
rPFS in these patients.
Study objective
Objectives
Primary
* To determine the efficacy (as assessed by radiographic progression free
survival [rPFS]) of AZD4635 plus durvalumab and separately of AZD4635 plus
durvalumab plus cabazitaxel in participants with mCRPC.
Secondary
* To evaluate the safety and tolerability of each treatment regimen in
participants with mCRPC.
* To determine the efficacy of AZD4635 plus durvalumab and separately of
AZD4635 plus durvalumab plus cabazitaxel by assessment of overall survival (OS)
in participants with mCRPC.
* To determine the efficacy of AZD4635 plus durvalumab and separately of
AZD4635 plus durvalumab plus cabazitaxel, by assessment of ORR in participants
with mCRPC.
* To determine the efficacy of AZD4635 plus durvalumab and separately of
AZD4635 plus durvalumab plus cabazitaxel by assessment of DoR in participants
with mCRPC.
* To determine the efficacy of AZD4635 plus durvalumab and separately of
AZD4635 plus durvalumab plus cabazitaxel, by assessment of PSA response in
participants with mCRPC.
* Investigate the PK of AZD4635 when given in combination with durvalumab, and
when given in combination with durvalumab plus cabazitaxel.
* To determine the efficacy of AZD4635 plus durvalumab and AZD4635 plus
durvalumab plus cabazitaxel in participants with mCRPC, by adenosine (ADO)
signalling gene expression in high and low subgroups in each arm separately.
* To determine the efficacy of AZD4635 plus durvalumab and AZD4635 plus
durvalumab plus cabazitaxel in participants with mCRPC, by adenosine deaminase
(ADA) gene expression in high and low subgroups in each arm separately.
* To determine the effects of AZD4635 on pain and other prostate cancer related
symptoms.
Exploratory
* Evaluate response using a modified RECIST criteria for immunotherapy (iRECIST)
* Investigate the impact of genomic status on the participant response to the
treatment combinations.
* DNA for future exploratory research into genes/genetic variations that may
influence response (i.e., distribution, safety, tolerability, and efficacy) to
AZD4635 treatment.
* To investigate baseline circulating tumour DNA (ctDNA), as well as changes in
ctDNA levels with treatment for correlation with tumour burden.
* Evaluation of prostatic acid phosphate (PAP) levels and activity.
* To explore the relationship between PK parameters and selected endpoints
(which may include PD/biomarker, efficacy, and/or safety), where deemed
appropriate.
Study design
This is a Phase II, international, open-label, two-arm, non-randomised study of
AZD4635 in participants with mCRPC. The primary objective is to determine the
rPFS of AZD4635 plus durvalumab (Arm A) and separately of AZD4635 plus
durvalumab plus cabazitaxel (Arm B) (see Figure 1 in the protocol).
Participants in each arm will be stratified by the presence of measurable soft
tissue metastasis (per RECIST v1.1, Appendix F of the protocol) or bone-only
metastasis (per PCWG3 criteria, Appendix H of the protocol). There will be no
formal comparisons between treatment arms. Secondary endpoints include; safety,
OS, confirmed ORR, DoR, confirmed PSA50 response, time to pain progression, and
PK.
AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80
participants mCRPC previously treated with docetaxel and one prior NHA (either
abiraterone acetate or enzalutamide but not both; prior apalutamide is not
permitted in Arm B).
Eligible participants must have histologically diagnosed mCRPC with no evidence
of small cell histology, have had progression of disease * 6 months prior to
study entry either by RECIST v1.1 or bone lesions per PWCG3 and have ongoing
androgen deprivation with serum testosterone < 50 ng/mL.
Participants will be allocated to one of the following treatment arms:
Arm A: AZD4635 (75 mg PO daily) plus durvalumab (1500 mg IV Q4W) (n = 80)
or
Arm B: AZD4635 (75 mg PO daily) plus durvalumab (1500 mg IV Q3W) plus
cabazitaxel (20 or 25 mg/m2 IV Q3W as per local prescribing guidelines) (n =
80).
Participants in Arm B will receive cabazitaxel chemotherapy as per the local
label. This will start approximately 1 hour (or up to a maximum of 2 hours)
after the end of the durvalumab infusion. Cabazitaxel will be administered as
per the local prescribing guidelines for a maximum of 10 cycles. After cycle 10
durvalumab + AZD4635 will be administered Q4W to harmonise with the Arm A
treatment cycle length.
Treatment in group A is only proposed to patients already enrolled in this
study group, because enrollment in group A is closed.
Arm B participants must receive premedication to manage cabazitaxel-associated
reactions (hypersensitivity or other):
* Prednisone (10 mg daily continuously [or equivalent steroid]) for the
duration of cabazitaxel administration
* Primary G-CSF prophylaxis (G-CSF should be administered according to the
product label and institutional standards).
An archival tumour sample is required or the participant must be willing to
undergo a baseline tumour biopsy (see Section 8.6.1.3 of the protocol). The
collection of paired tumour biopsies will be requested during the study;
however, this is optional (see Section 8.6.2.1 of the protocol).
Participants in Arm A (AZD4635 plus durvalumab) will have disease
assessments/imaging at baseline and every 8 weeks (± 7 days) from the start of
dosing for the first 24 weeks and then every 12 weeks (± 7 days) thereafter.
During the study, tests for active COVID-19 infection may be prescribed, if
required, and in accordance with local guidelines.
If a participant is symptomatic for active COVID-19 infection during a site
visit, he may be prescribed a COVID-19 test. Dosing may continue while results
are awaited, per the Investigator*s discretion and local guidelines, and the
Medical Monitor/AstraZeneca Study Physician should be consulted. For
participants who test positive (for COVID-19) the study drugs may be
temporarily interrupted and later resumed, per the Investigator*s discretion
and local guidelines, and this should be discussed with the Medical
Monitor/AstraZeneca Study Physician. Where applicable, home or remote visits
may be conducted for study assessments and study drug administration (see
Appendix L of the protocol).
Participants in Arm B (AZD4635 plus durvalumab and cabazitaxel) will have
disease assessments/imaging at baseline and every 9 weeks (± 7 days) from the
start of dosing for the first 27 weeks and then every 12 weeks (± 7 days)
thereafter. A safety assessment to determine the safety and tolerability of
this combination will be completed by the SRC after the first 6 participants
have completed a safety assessment period of at least 1 cycle (see Section
4.1.1 of the protocol).
The participant reported outcome (PRO) instruments, a BPI-SF (see Appendix J)
and FACT P (see Appendix K) will be administered to all participants. These two
instruments will be used to assess pain and quality of life in study
participants. These will be measured as shown in Table 1*1 and Table 1*2 of the
protocol
The two arms will enrol and assign to study treatment approximately 160
participants (80 per arm) with metastatic disease documented by either bone
lesions on bone scan or with soft tissue disease that is evaluable for
assessment. At least 40 participants with RECIST v1.1 measurable disease
(Section 5.1 of the protocol) at baseline will be enrolled and assigned to
study treatment in each arm, and the remainder of participants in the arm (n=40
per arm) may have bone-only disease or measurable disease. The primary
analysis, rPFS, will be assessed, and is defined as the time from first dose to
radiographic progression as determined by the Investigator per RECIST v1.1 for
soft tissue disease or PCWG3 for bone disease or death from any cause,
whichever occurs first. Overall survival, ORR, DoR, PSA50 response, and time to
pain progression will also be evaluated for efficacy.
Intervention
Study intervention in this study refers to AZD4635, durvalumab and cabazitaxel.
In this protocol AZD4635, durvalumab and cabazitaxel are also referred to as
either study drugs, study interventions, IPs, or investigational medicinal
products * and these terms are used interchangeably.
Arm A: AZD4635 capsules will be taken by mouth once daily.
Durvalumab will be given via an IV at the study site once every 4 weeks (every
cycle).
If the patient's previous treatment included docetaxel and one NHA (e.g.,
abiraterone acetate or enzalutamide but not both), you will be treated
according to Arm B (AZD4635, durvalumab and cabazitaxel).
Arm B:
AZD4635 capsules will be taken by mouth once daily.
Durvalumab will be given via an IV at the study site once every 3 weeks (every
cycle).
Treatment with AZD4635 and durvalumab will continue after Cycle 10, with
durvalumab given once every 4 weeks thereafter.
Cabazitaxel will be given via an IV at the study site once every 3 weeks (every
cycle).
Treatment in group A is only proposed to patients already enrolled in this
study group, because enrollment in group A is closed.
Prednisone will be taken by mouth once daily, for as long as you are receiving
cabazitaxel, to lessen side effects associated with cabazitaxel.
Cabazitaxel will be administered as per standard treatment, for a maximum
duration of 10 cycles (approximately 7.5 months). Treatment with AZD4635 and
durvalumab will continue, but treatment with durvalumab will be adjusted to
every 4 weeks, instead of every 3 weeks.
Granulocyte-colony stimulating factor (G-CSF) will be given during the cycles
in which cabazitaxel is given. G-CSF is given to lessen the chance of infection
caused by cabazitaxel chemotherapy. G-CSF will be monitored and administered
by the study doctor.
Study burden and risks
Data from treatment with AZD4635 alone in 141 subjects as of 02 December 2019
showed.
AZD4635 side effect(s)
Very common (seen in more than 1 in 10 people)
Nausea
Fatigue/Tiredness
Vomiting
Decreased appetite
Dizziness
Diarrhoea
Common (seen between 1 in 20 and 1 in 10 people)
Altered sense of taste
Risks associated with the combination of AZD4635 and durvalumab
The combination of AZD4635 and durvalumab is being evaluated in ongoing
studies. It is possible that the combination may lead to side effects related
to immune reactions, which are known to occur with durvalumab. In an ongoing
study, two patients developed type 1 diabetes when AZD4635 was taken in
combination with durvalumab.
Overlapping side effects to date include nausea, fatigue, vomiting,
constipation, diarrhea, decreased appetite, stomach pain, dehydration, muscle
aches, and depression. The side effects can be worse or different than if the
patient takes either drug by itself. Patients will be closely monitored during
therapy.
Potential risk associated with the combination of AZD4635, durvalumab and
cabazitaxel
It is possible that the combination of study drugs used in this study may lead
to increased severity and incidence of side effects related to febrile
neutropenia - a condition marked by fever and a lower-than-normal number of
neutrophils in the blood. A neutrophil is a type of white blood cell that helps
fight infection and having too few neutrophils can increase the risk of
infection.
Durvalumab
Most of the possible side effects listed below are mild to moderate. However,
some side effects can be very serious and life-threatening and may even result
in death. Some side effects do not need treatment, while others generally get
better with treatment. The patient may need to delay doses of durvalumab to
allow the side effects to get better. Management of these side effects may also
require the administration of drugs such as steroids or other agents that can
affect the patient's immune system and reduce inflammation.
Durvalumab side effect(s)
Very common (seen in more than 1 in 10 people)
Diarrhea
Rash/Dry itchy skin
Abdominal pain
Upper respiratory tract infections
Cough
Fever
Underacitve thyroid gland that causes tiredness or weight gain (hypothyroidsm)
Durvalumab side effect(s)
Common (seen in more than 1 in 100 people)
Inflammation in the lungs (pneumonitis)
Overactive thyroid gland that can cause fast heart rate or weight loss
Changes in lab tests related to kidney and liver function
Infusion-related reactions
Pain in muscles and joints (myalgia)
Pneumonia
Influenza
Hoarse voice
Painful urination
Night sweats
Fungal infection in the mouth (oral candidiasis)
Dental and soft tissue infections
Accumulation of fluid causing swelling in the legs
Cabazitaxel
Cabazitaxel is an anti-cancer medication given with the medication prednisone.
It is approved and licensed to treat men with prostate cancer that has worsened
(progressed) after treatment with other anti-cancer medicines, including
docetaxel. The side effects associated with cabazitaxel are recorded in the
prescribing information.
Cambridge CB21 -
Cambridge 6GH
GB
Cambridge CB21 -
Cambridge 6GH
GB
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
Age
1 Participant must be 18 years of age inclusive at the time of signing the
informed consent.
Type of Participant and Disease Characteristics
2 Histologically confirmed adenocarcinoma of the prostate
* Disease must be metastatic and inoperable and for which there is no curative
intervention available. Participants may have bone-only disease.
* Participants presenting with treatment-emergent neuroendocrine
differentiation, but not primary small-cell features, are eligible.
3 Known castrate-resistant disease, defined as:
* Testosterone level in the castration range (levels < 50 ng/dl) because of a
previous, and ongoing, androgen-deprivation with luteinizing hormone-releasing
hormone (LHRH) agonists or antagonists or bilateral orchiectomy. Participants
must have developed progression of metastases following surgical castration or
during medical androgen ablation therapy. Participants receiving medical
castration therapy with gonadotropin-releasing hormone (GnRH) analogues should
continue this treatment during this study.
4 Evidence of disease progression * 6 months defined by one or more of the
following:
* Progression as defined by RECIST v1.1 criteria for assessment of malignant
soft tissue disease and lymph nodes
* Progression of bone lesions on bone scan from a previous or baseline
assessment per PCWG3
* Rising PSA defined as at least two consecutive rises in PSA to be documented
over a reference value (measure 1) taken at least 1 week apart. The first
rising PSA (measure 2) should be taken at least 7 days after the reference
value. A third confirmatory PSA measure is required (2nd and beyond the
reference level) to be greater than the second measure and it must be obtained
at least 7 days after the 2nd measure. If this is not the case, a fourth PSA
measure is required to be taken and be greater than 2nd measure. The third (or
the fourth) confirmatory PSA should be taken within 4 weeks prior to study
entry.
5 Must have measurable disease:
* At least 1 documented lesion on either a bone scan or a computed tomography
(CT)/magnetic resonance imaging (MRI) scan that can be followed for response is
suitable for repeated measurement
Or
* Non-measurable disease must have measurable PSA * 1.0 ng/mL as the minimum
starting level for trial entry if the confirmed rise is the only indication of
progression (excluding small cell carcinoma).
Weight
6 Body weight > 30 kg at screening.
Reproduction
7 Willingness to adhere to the study treatment-specific contraception
requirements: Participants must be surgically sterile or using an acceptable
method of contraception (defined as a male condom in conjunction with
spermicides) for the duration of the study (from the time they sign ICF) and
for 12 weeks (3 months) after the last dose of AZD4635 and/or durvalumab and
for 24 weeks (6 months) after the last dose of cabazitaxel to prevent pregnancy
in a female partner. Participants must not donate or bank sperm for 24 weeks
after treatment. The reporting of any pregnancy in the female partner of a
participant is described in Section 8.3.9.1 of the protocol.
Bone Marrow Reserve and Organ Function
8 Adequate bone marrow reserve and organ function as demonstrated by all of the
following laboratory values:
* Absolute neutrophil count (ANC) * 1.5 × 109/L
* Platelet count * 100 × 109/L
* Haemoglobin * 9.0 g/dL (* 10.0 g/dL for Arm B)
* Creatinine * 1.5 × ULN concurrent with creatinine clearance > 50 mL/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is > 1.5 × ULN.
Additional Inclusion Criteria Specific for Arm A
9 Adequate organ function for Arm A as demonstrated by all of the following
laboratory values:
* Alanine aminotransferase (ALT) * 2.5 × the upper limit of normal (ULN) if no
demonstrable liver metastases or * 5 × ULN in the presence of liver metastases.
* Aspartate aminotransferase (AST) * 2.5 × ULN if no demonstrable liver
metastases or * 5 × ULN in the presence of liver metastases
* Total bilirubin (TBL) * 1.5 × ULN
* TBL * 2.0 × ULN in the case of known Gilbert syndrome with normal direct
bilirubin
10 Participants in Arm A must have received the following prior therapy:
* Maximum of 3 lines of therapy in the mCRPC setting
* Prior therapy with one or more NHAs (e.g., abiraterone acetate, enzalutamide,
apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory
settings
* Prior therapy with one or more lines of taxanes (e.g., docetaxel and/or
cabazitaxel)
* Alternatively, must be taxane-ineligible
* Prior therapy can be in either the hormone-sensitive or the
hormone-refractory setting
* Patients who were eligible for both Arm A and Arm B will be preferentially
allocated to Arm B, until enrollment of Arm B is completed.
Additional Inclusion Criteria Specific for Arm B
11 Adequate organ function for Arm B as demonstrated by all of the following
laboratory values:
* AST and/or ALT * 1.5 × ULN
* TBL * ULN
* TBL * 2.0 × ULN in the case of known Gilbert syndrome with normal direct
bilirubin
12 Participants in Arm B must have received the following prior therapy:
* Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory
settings
* Received no prior cytotoxic chemotherapy other than docetaxel for prostate
cancer except for estramustine and except adjuvant/neo-adjuvant treatment
completed > 3 years ago.
* Prior therapy with only one NHAs (e.g., abiraterone acetate or enzalutamide;
prior apalutamide is not permitted) for treatment of mCRPC in either
hormone-sensitive or hormone-refractory settings.
* Be suitable to receive concomitant GCSF during all cycles of cabazitaxel.
* Participants who meet inclusion criteria for Arm B will be allocated
preferentially to that arm until recruitment to that arm is completed.
Other Inclusion Criteria
13 World Health Organisation (WHO) performance status of 0-1 with no clinical
deterioration over the previous 2 weeks prior to the 28-day screening period
and likely able to complete at least 12 weeks of treatment.
14 Normotensive or well controlled blood pressure (BP) (systolic < 150 and
diastolic < 90), with or without current antihypertensive treatment. If there
is a diagnosis or history of hypertension, participant must have adequately
controlled BP on antihypertensive medications.
15 Availability of an archival tumour sample. If an archival tumour sample is
not available, then a tumour biopsy will be required to obtain a tumour sample.
16 Participants must be able to swallow and retain oral medications (e.g.,
AZD4635 and/or prednisone).
Informed Consent
1 Capable of giving signed informed consent as described in Appendix A and able
to comply with the requirements and restrictions listed in the informed consent
form (ICF) and in this protocol
2 Provision of signed and dated written Optional Genetic Research Information
informed consent prior to collection of samples for optional genetic research
that supports Genomic Initiative
Exclusion criteria
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1 Active brain metastases or leptomeningeal metastases. Participants with brain
metastases are eligible if treated and there is no evidence of progression for
at least 8 weeks after treatment is completed and within 28 days prior to the
first dose of study intervention.
2 There must be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone/equivalent) for at least 2 weeks prior
to study enrollment. For current or prior use of immunosuppressive medication
within 14 days before the first dose the following will be exceptions to this:
* 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)
3 Participant with a history of pneumonitis.
4 History of a second malignancy that is progressing and/or received active
treatment * 3 years before the first dose of study intervention.
5 As judged by the Investigator, any evidence of severe or uncontrolled
systemic diseases, including uncontrolled hypertension, active bleeding
diatheses, active infection including hepatitis B, hepatitis C, and human
immunodeficiency virus, chronic gastrointestinal diseases (e.g., Crohn's
disease, chronic colitis), ongoing or active infection, symptomatic congestive
heart failure, uncontrolled hypertension, unstable angina pectoris,
uncontrolled cardiac arrhythmia, or active interstitial lung disease (ILD).
Screening for chronic conditions is not required.
6 Creatinine clearance < 50 mL/min (calculated by Cockcroft-Gault equation).
7 Prior exposure to immune-mediated therapy including, but not limited to
anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding
therapeutic anti-cancer vaccines.
8 History of allogeneic organ transplantation.
9 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:
* Participants with vitiligo or alopecia
* Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable
on hormone replacement
* Any chronic skin condition that does not require systemic therapy
* Participants without active disease in the last 5 years may be included but
only after consultation with the Study Physician
* Participants with coeliac disease controlled by diet alone
10 History of active primary immunodeficiency.
11 Active infection including tuberculosis (clinical evaluation that may
include clinical history, physical examination and radiographic findings, and
tuberculosis testing in line with local practice).
12 Receipt of live attenuated vaccine within 30 days prior to the first dose of
study intervention.
Additional Exclusion Criteria Specific for Arm B: Medical Conditions
13 Participant with active grade * 2 peripheral neuropathy
14 Participant with active grade * 2 stomatitis
Prior/Concomitant Therapy
15 Any small-molecule, biologic, or hormonal agent from a previous treatment
regimen or clinical study within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of study intervention. At least 7 days must have
elapsed between the last dose of such agent and the first dose of study
intervention. Exception: androgen-deprivation therapy is permitted.
16 History of hypersensitivity to any of the study drugs or any of the study
drug excipients including hypersensitivity to polysorbate-80 if allocated to
cabazitaxel.
17 Nitrosourea or mitomycin C within 6 weeks of the first dose of study
intervention.
18 Prescription or non-prescription drugs or other products known to be
sensitive BCRP, OATP1B1/3, OAT1, OCT1, OCT2, MATE1 and P-gp substrates or to be
strong inhibitors/inducers of CYP1A2 (see Appendix I), which cannot be
discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the
study, until 2 weeks after the last dose of study intervention.
19 Exclusion Criteria for Arm B: Concurrent or planned treatment with strong
inhibitors or strong inducers of cytochrome P450 3A4/5 (CYP3A4/5) are excluded
(a 2-week washout period is required for participants already on these
treatments) (see Appendix I).
20 Herbal preparations/medications are not allowed throughout the study. These
herbal medications include but are not limited to St. John*s wort, kava,
ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw
palmetto, and ginseng. Participants should stop using these herbal medications
7 days prior to the first dose of study intervention. Exceptions may be agreed,
but the circumstances must be reviewed by the Medical Monitor/AstraZeneca Study
Physician in advance.
21 Ongoing treatment with warfarin (Coumadin).
22 Major surgery (excluding placement of vascular access) within 4 weeks of the
first dose of study intervention.
23 Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy
with a limited field of radiation for palliation within 2 weeks of the first
dose of study intervention.
Prior/Concurrent Clinical Study Experience
24 AZD4635 in the present study (i.e., dosing with AZD4635 previously initiated
in a different arm in this study) or prior therapy with AZD4635 or any other
A2AR antagonist or other CD73/CD39 antagonists.
25 History of allogeneic organ, or other transplant, such as bone marrow
transplant.
26 With the exception of alopecia, any unresolved toxicities from prior therapy
greater than Common Terminology Criteria for Adverse Events (CTCAE), Version
5.0 Grade 1 at the time of starting study treatment. Participant with chronic
Grade 2 unresolved toxicities may be eligible following discussion with the
Medical Monitor/AstraZeneca Study Physician.
27 Concurrent enrollment into another therapeutic clinical trial.
28 Concomitant treatment with another adenosine 1 receptor (A1R) antagonist
that would increase risk of seizure (e.g., theophylline, aminophylline).
Diagnostic Assessments
29 Any of the following cardiac criteria:
* Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 ECGs
* Any clinically important abnormalities in rhythm, conduction, or morphology
of resting ECGs, e.g., complete left bundle branch block, third-degree heart
block
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, or
family history of long QT syndrome or unexplained sudden death under 40
years-of-age
* Ejection fraction < 55% or the lower limit of normal of the institutional
standard, ascertained by an echocardiogram or multiple-gated acquisition (MUGA)
that has been obtained in the 6 months prior to screening. If there has been a
change in the participant*s cardiac status, or if there has not be an
echocardiogram or MUGA within the 6 months prior to study enrollment, this
should be performed as part of the screening assessments.
Other Exclusions
30 Judgment by the Investigator that the participant should not participate in
the study if the participant is unlikely to comply with study procedures,
restrictions and requirements.
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 | EUCTR2020-000209-10-NL |
| ClinicalTrials.gov | NCT04495179 |
| CCMO | NL75405.028.20 |