Primary objective To investigate the safety and tolerability of CCS1477 as monotherapy and in combination.
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective
To investigate the safety and tolerability of CCS1477 as monotherapy and in
combination.
Secondary outcome
Secondary objectives
- To obtain a preliminary assessment of the anti-tumour activity of CCS1477
- To characterize the pharmacokinetics (PK) of combination agents when dosed in
combination with CCS1477 to investigate any drug-drug interactions.
Exploratory objectives
- To explore the relationship between PK, safety, efficacy and blood borne and
tissue biomarkers, if appropriate.
- To collect and store blood and tumour samples for exploratory biomarker
analysis
- To investigate the presence, and/or identity of drug metabolites of CCS1477
and, if appropriate, characterise their PK.
Background summary
BACKGROUND
Prostate cancer is the most common form of malignancy in men and is the second
leading cause of male cancer-related death, with approximately 47,000 new cases
and 11,000 deaths annually in the UK alone1. It is the 2nd commonest cancer
overall (behind breast cancer) and the 3rd leading cause of cancer death in
U.S. men behind lung and colorectal cancer. At diagnosis approximately 79% of
patients have localised disease (confined to the prostate gland) while
approximately 12% have regional disease (spread beyond the prostate to local
lymph nodes) and 4% have distant metastatic disease (spread to distant
anatomical sites). The 5-year survival for localised, regional and metastatic
disease are 100%, 100% and 29.8% respectively.
The choice of treatment for patients with mCRPC largely depends on the presence
or absence of symptoms and the extent and location of metastases. These
treatment options include
-Abiraterone (androgen biosynthesis inhibitor), enzalutamide (androgen receptor
inhibitor) for patients with asymptomatic or mildly asymptomatic disease.
- Sipuleucel-T (autologous cellular immunotherapy targeted against prostatic
acid phosphatase) for patients with asymptomatic or mildly asymptomatic disease
- Radium-223 (targeted alpha emitter that selectively binds to areas of
increased bone turnover in bone metastases) in patients with symptomatic and
predominantly bone metastases
- Docetaxel (chemotherapy) in patients with significantly symptomatic disease
(including visceral metastases)
- Patients previously treated with docetaxel may be treated with any treatments
which they have not previously received (abiraterone, enzalutamide, radium-
233, and cabazitaxel (2nd generation taxane chemotherapy)
There is now a substantial body of evidence demonstrating that disease
progression after ADT is dependent on ongoing signalling through the AR via a
number of different but related mechanisms. These include:
- An increase in the expression of AR through genomic AR amplification, which
can sensitise prostate cells to low levels of androgen
- AR activating mutations that cause AR antagonists to behave as agonists or
the AR to respond to alternative ligands
- Alternative splicing of AR to produce constitutively active forms of AR that
lack the ligand binding domain
- Increased expression of AR co-regulators
- Increased androgen generation within prostate tumours
Understanding of the central role of the AR in prostate cancer has led to the
development of second generation anti-androgen drugs, notably abiraterone and
enzalutamide. Both drugs are approved for the treatment of patients with
mCRPC, based on an improvement in overall survival. However, these therapies
are not curative and further resistance occurs, again mediated by restored AR
pathway activation.
When tumours are exposed to AR antagonists, mutations can arise in the
ligand-binding domain of the AR that are specific to the anti-androgen therapy
that the patients have been receiving. These mutations result in the
anti-androgen acting to promote rather than block AR signalling. Expression of
constitutively active splice variant forms of the androgen-receptor (AR-SV) is
another important mechanism of resistance to drug treatment. AR-V7 is the
best-characterised of the many different AR-SV forms, all of which lack the
ligand-binding domain (LBD), but retain the deoxyribonucleic acid (DNA)-binding
domain of the receptor8. Treatments that target the LBD, including
anti-androgens such as enzalutamide, are ineffective on AR-SVs. Thus, whilst
focusing in on the AR is key, there is a clear need to develop new approaches
beyond specifically targeting the LBD with capability to inhibit the major
mechanisms of resistance at the same time.
One such approach is to target key co-regulators of AR structure and function.
P300 and CBP are two closely related histone acetyltransferase (HAT) proteins
that are critical transcriptional co-regulators of the AR. Both are believed
to be oncogenic in prostate cancer and are up-regulated during disease
progression. P300/CBP have two main functions:
- to acetylate key client proteins such as the AR, and
- to act as part of a complex of proteins including the AR, which enhances
transcription of AR target genes
Inhibiting p300/CBP would be expected to inhibit both the expression and
function of AR. Importantly, because the mode of action does not involve
interaction with the LBD of the AR, inhibition of p300/CBP should be effective
against tumours with amplified AR, AR-mutations and AR splice variants.
In addition to the critical role that p300/CBP plays in co-regulating the AR,
it is also becoming increasingly evident that certain other tumours may be
particularly sensitive to p300/CBP inhibition. Tumours that harbour loss of
function mutations in either p300 or CBP become dependent on the corresponding
non-mutated paralogue (twin) protein for their continued growth. When the
non-mutated twin is inhibited, this drives synthetic lethality leading to
apoptosis/cell death. In lung cancer, genetic analysis reveals that up to 15%
of both non-small cell and small cell tumours have these loss of function
mutations. Similar mutations are also found in up to 25% of bladder cancers,
as well as in a number of haematological malignancies. It has been shown that
CCS1477 has selective anti-proliferative activity in a range of cancer cell
lines which have loss of function mutations in either p300 or CBP.
Other cancer cell lines also demonstrate sensitivity to CCS1477; the underlying
molecular determinants of this have yet to be determined, but may include
over-expression of c-Myc and expression of AR in tumours other than prostate
such as breast. Thus, beyond CRPC, CSS1477 has the potential to benefit
patients with a range of malignancies.
Study objective
Primary objective
To investigate the safety and tolerability of CCS1477 as monotherapy and in
combination.
Study design
This is a phase I/IIa open-label, multicentre study of CCS1477 administered as
monotherapy or in combination with abiraterone or enzalutamide in patients with
mCRPC, and as monotherapy in patients with advanced solid tumours with
molecular markers which may indicate potential for response to p300/CBP
inhibition.
There are multiple parts to this study.
Monotherapy Dose Escalation
Part A - CCS1477 monotherapy dose escalation in patients with mCRPC to
determine the maximum tolerated dose (MTD) or the recommended dose and schedule
of CCS1477 monotherapy (RP2D-M).
Initially dose escalation will involve a single patient cohort design (until a
related toxicity >= CTCAE Grade 2 is observed) to minimise the number of
patients exposed to potentially sub-therapeutic doses. The study will then
switch to a modified rolling 6 design in which 3-6 patients will be enrolled
into each cohort.
• Parts B1 and B2 - CCS1477 monotherapy expansion cohorts in patients with
mCRPC, 2 different doses and/or schedules may be tested.
• Part C has two parts, conducted in sequence:
Part C1 - CCS1477 in combination with abiraterone in patients with mCRPC
(combination dose finding), intended to establish the recommended phase II dose
and schedule for CCS1477 in combination with abiraterone (RP2D-Cabi)
Part C2 - combination therapy expansion cohort
• Part D has two parts, conducted in sequence:
Part D1- CCS1477 in combination with enzalutamide in patients with mCRPC
(combination dose finding), intended to establish the recommended phase II dose
and schedule for CCS1477 in combination with enzalutamide (RP2D-Cenz), which
may be the same as RP2D-Cabi
Part D2 - combination therapy expansion cohort
• Part E has 2 parts:
Part E1 - Monotherapy CCS1477 in patients with advanced solid tumours with
molecular markers which may indicate potential for response to p300/CBP
inhibition. Patients can be entered into Part E1 during the dose escalation
phase of the study and will receive CCS1477 at a dose and schedule which has
been previously declared tolerated during the ongoing Part A dose escalation
phase.
Part E2 - Monotherapy CCS1477 exploratory expansion in patients with advanced
solid tumours with molecular markers which may indicate potential for response
to p300/CBP inhibition. Patients will be entered into Part E2 following the
completion of Part A using data from Part A and Part E1 to establish the best
dose for Part E2.
•Part F has 2 parts:
Part F1 will establish the recommended dose and schedule of CCS1477 in
combination with darolutamide in patients with mCRPC who have previously
received abiraterone and/or enzalutamide (or equivalent anti-androgen)
treatment and have received, or are ineligible for, treatment with a taxane,
will be assessed.
Part F2 is an expansion phase which will recruit approximately 25 mCRPC
patients to investigate the clinical activity of the RP2D of CCS1477 in
combination with darolutamide
• Part G has 3 parts:
Part G1 will establish the recommended dose and schedule of CCS1477 in
combination with olaparib in patients with either mCRPC or locally advanced or
metastatic breast cancer.
Part G2 is an expansion phase which will recruit approximately 25 mCRPC
patients to investigate the clinical activity of the combination of the RP2D of
CCS1477 in combination with olaparib (mCRPC patients from Part G1 may be
included in this number).
Part G3 is an expansion phase which will recruit approximately 25 metastatic
breast cancer patients to investigate the clinical activity of the combination
of the RP2D of CCS1477 in combination with olaparib
• Part has 2 parts:
Part H1 will establish the recommended dose and schedule of CCS1477 in
combination with atezolizumab in patients with locally advanced or metastatic
NSCLC after prior chemotherapy
Part H2 is an expansion phase which will recruit approximately 25 patients with
locally advanced or metastatic NSCLC after prior chemotherapy to investigate
the clinical activity of the combination of the RP2D of CCS1477 in combination
with atezolizumab
There will be no randomisation in this study.
Intervention
Open label study. Each part of the study will have treatment with CCS1477.
Part A: Monotherapy CCS1477 Dose Escalation -> completed as of 14April 2021
Part B: Monotherapy CCS1477 Expansion
Part C1 and C2: CCS1477 in combination with abiraterone
Part D1 and D2: CCS1477 in combination with enzalutamide
Part E: Monotherapy CCS1477 Expansion
Part F1 and F2: CCS1477 in combination with darolutamide
Part G1: CCS1477 in combination with olaparib in patients with either mCRPC or
locally advanced or metastatic breast cancer.
Part G2: Expansion CCS1477 in combination with olaparib (mCRPC patients)
Part G3: Expansion CCS1477 in combination with olaparib (metastatic breast
cancer)
Part H1: CCS1477 in combination with atezolizumab in patients with locally
advanced or metastatic NSCLC
Part H2: Expansion CCS1477 in combination with atezolizumab in patients with
locally advanced or metastatic NSCLC
Study burden and risks
CCS1477 has the potential to provide clinical benefit to patients who have
progressed after treatment with 2nd generation anti-androgen therapies such as
abiraterone or enzalutamide. The mechanisms by which tumours become resistant
to 2nd generation anti-androgen therapies include the generation of activating
mutations and splice variant forms of the AR, which drive disease progression.
CCS1477 works by down-regulating the expression and function of all forms of
the AR, including mutated and splice variant AR and has anti-tumour activity in
models of CRPC, where abiraterone or enzalutamide are ineffective.
Preliminary signals of activity have been seen in some patients in dose
escalation cohorts.
CCS1477 in combination with abiraterone or enzalutamide has the potential to
provide superior clinical benefit to patients compared with either
anti-androgen therapy given alone. CCS1477 and abiraterone or enzalutamide,
target independent but complimentary mechanisms that regulate AR expression and
function and would therefore be expected to give enhanced anti-tumour activity
when combined by more effectively supressing the AR pathway. Anti-tumour
activity is greater in CRPC models that are responsive to enzalutamide when
CCS1477 is combined with enzalutamide vs enzalutamide given alone.
CCS1477 has the potential to provide clinical benefit to patients with advanced
solid tumours with molecular markers which may indicate potential for response
to p300/CBP inhibition. CCS1477 is active in certain cell lines that have
mutations in p300/CBP compared with cell lines without the mutations or in cell
lines that over-express AR or are c-Myc dependent. .
Potential risks
The preclinical and emerging safety profile has not identified any risks that
would preclude investigation of CCS1477 in the advanced cancer setting.
P300/CBP is known to play a role in haematopoiesis. Impact on haematological
parameters, including a reduction in platelets with corresponding pathological
changes in lymphoid tissues including the bone marrow, was observed in both
rats and dogs dosed with CCS1477. In the pre-clinical studies the reduction in
platelets emerges after several days of treatment in some animals, with the
nadir being observed after 14 days of continuous dosing in the rats.
Interruption of CCS1477 led to recovery in platelet numbers and re-treatment
with CCS1477 did not lead to a worsening of effect. Based on the preclinical
studies, other haematological abnormalities may be observed including possibly
anaemia and lymphopenia. Patients will have regular planned haematology
assessment (including platelet count estimation) and will be informed and asked
to report any symptoms or signs of bleeding (easy bruising, petechiae etc).
Appropriate treatment will be administered as needed (CCS1477 dose interruption
and platelet transfusions).
P300/CBP is known to cause an effect on the AR. Atrophy of androgen-dependent
tissues, including lymphoid tissues and reproductive organs, were observed in
both the rat and the dog after dosing CCS1477. These changes are considered to
be a direct consequence of on-target pharmacology. Atrophic changes may also
be seen in male reproductive organs associated with symptoms and signs of
androgen deprivation. Although part of the desired mechanism of action for
patients with CRPC, such changes may be unwanted in males with other tumours
enrolled in the study. Serum luteinizing hormone (LH), follicular stimulating
hormone (FSH) and testosterone (male patients only) will be measured at
screening and on study treatment, and CCS1477-related symptoms or signs
consistent with androgen deprivation (including but not limited to decreased
libido, erectile dysfunction, gynaecomastia, fatigue, depression,
osteopenia/osteoporosis and anaemia) will be monitored during the study.
Changes in electrolytes (slight increase in plasma potassium, sodium and
calcium concentrations) were observed after 28 days dosing in the rat. As a
result of prolonged changes in electrolyte concentrations, minimal vacuolation
and degeneration in the kidney was observed at the highest dose level in the
rat. Electrolyte concentrations in patients will be monitored, with
appropriate action taken if needed.
The current emerging clinical safety profile is generally in line with the
pre-clinical safety, with haematological toxicity (predominantly
thrombocytopenia) and electrolyte disturbances (mainly hyponatremia), which are
reversible with treatment interruption and/or intervention. Important potential
risks consistent with preclinical data continue to be carefully monitored in
clinical data and one new potential risk (gastrointestinal toxicity) has been
identified during the reporting*period*based on*clinical*data and literature
report for another investigational compound inhibiting p300/CBP.
Chesterford Research Park, Little Chesterford NA
Cambridge CB10 1XL
GB
Chesterford Research Park, Little Chesterford NA
Cambridge CB10 1XL
GB
Listed location countries
Age
Inclusion criteria
1. Written informed consent;
2. willing and and able to comply with study protocol procedures
3. >= 18 years
4. ECOG performance status 0-1 with no deterioration over previous 2 weeks and
minimum life expectancy of 12 weeks
5. Adequate organ functions:
• AST/ALT <=3 x ULN or AST/ALT <=5 x ULN
• Total bilirubin <=1.5 x ULN (or <3 UNL if bilirubin rise is due to Gilbert's
syndrome or of non-hepatic origin, or due to underlying liver involvement).
• Calculated creatinine clearance by Cockcroft-Gault formula >=30 ml/min²
• ANC >=1.5 x 109/L
• Platelets >=100 x 109/L
• Haemoglobin >=9g/dL. (maintained without transfusion within 14 days of
starting CCS1477)
• Normal sodium level (patients with borderline sodium decrease below normal
level may be eligible following discussion with medical monitor).
• Serum albumin >2.5 g/dL
• LDH within normal level (patients with borderline LDH results may be eligible
following discussion with medical monitor)
6. For duration of the study and 1 week after the last study administration,
sexually active male patients must be willing to use barrier contraception with
all sexual partners. Where the sexual partner is a *woman of child-bearing
potential* who is not using effective contraception, men must use a condom and
another form of contraception during the study and for 6 months after the last
dose of study medication.
7. Females must agree to use highly effective contraceptive measures, must not
be breast feeding and must have a negative serum pregnancy test prior to start
of dosing if of child-bearing potential, or must have evidence of
non-child-bearing potential at screening per one of:
• Post menopausal defined as aged more than 50 years and amenorrhoeic for at
least 12 months following cessation of all exogenous hormonal treatments
• Documentation of irreversible surgical sterilisation by hysterectomy,
bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• Amenorrhoeic for 12 months and serum FSH, LH and plasma oestradiol levels in
the postmenopausal range for institution
8. Patients must have assessable disease (by CT, MRI, bone scan or X-ray) but
are not required to have measurable disease
Additional inclusion criteria for mCRPC patients (Parts A, B, C, D and F only)
9. Patients must have previously received standard available therapy including
(but not limited to):
• abiraterone and/or enzalutamide (or equivalent anti-androgen), and
• a taxane (unless ineligible)
10. Progressive disease documented by one or more of:
• Biochemical progression defined as at least 2 stepwise increases in a series
of any 3 PSA values collected while the patient has castrate levels of
testosterone. The 3 PSA values selected do not need to be consecutive, and do
not need to include the most recent PSA collected at, or prior to, study
enrolment, but must meet the following criteria:
a. PSA progression defined by minimum of 3 rising PSA levels with an interval
of >=1 week between each determination
b. Each of the 3 PSA values must be collected while the patient is under
medical castration or is surgically castrated
c. Ideally all 3 should be done after anti-androgen withdrawal (if applicable),
but they can be done during the withdrawal period
• Progression as defined by RECIST v1.1 guideline for assessment of malignant
soft tissue disease or modified RECIST v1.1 criteria as defined by PCWG-3 for
progression of nodes
• Progression defined as 2 or more new metastatic bone lesions confirmed on
bone scan from a previous assessment
11. PSA at screening must be >=2 µg/L (2 ng/mL)
12. Serum testosterone concentration <=50 ng/dL sustained by medical or surgical
castration
13. Serum albumin >2.5 g/dL
Additional Part C inclusion criteria (CCS1477 plus abiraterone)
14. Patients must have previously progressed on abiraterone treatment
15. Patients whose last dose of abiraterone is >6 months prior to start of
study treatment will receive a 4-week run-in treatment with abiraterone to
confirm refractoriness to abiraterone treatment
Additional Part D inclusion criteria (CCS1477 plus enzalutamide)
16. Patients must have previously progressed on enzalutamide treatment
17. Patients whose last dose of enzalutamide is >6 months prior to start of
study treatment will receive a 4-week run-in treatment with enzalutamide to
confirm refractoriness to enzalutamide treatment. All patients in drug-drug
interaction (DDI) arm will receive enzalutamide monotherapy during Cycle 0
Additional Part E inclusion criteria (non-prostate only)
18. Histological or cytological confirmation of malignancy that is advanced.
Patients must be refractory to, or intolerant of available therapies known to
provide clinical benefit for their condition
19. Identification of markers which may indicate potential for response to
p300/CBP inhibition will be determined by local testing and will include, but
not be limited to, loss of function mutations in either p300 or CBP and/or Myc
amplification or over-expression, determined by next generation sequencing in
tumour biopsies/cell free DNA extracted from a pre-treatment blood sample. IHC
may also be used, as appropriate, to determine over expression of proteins such
as myc or AR. Patients with certain cancers where molecular testing has not
been performed may be eligible upon discussion with medical monitor.
Additional inclusion criteria for patients in CCS1477 plus olaparib arm (Part G)
20. Patients receiving olaparib as standard of care (as per the local label).
Patients should not be responding sufficiently to treatment (in the opinion of
the investigator) within approximately 3 months of starting olaparib.
21. Patients should be tolerating treatment with olaparib and should be
continuing treatment with olaparib. Patients who have had a transient
interruption of treatment may be eligible following discussion with the medical
monitor.
Additional inclusion criteria for patients in CCS1477 plus atezolizumab arm
(Part H)
22. Patients with locally advanced or metastatic NSCLC after prior
chemotherapy. Patients with EGFR mutant or ALK-positive NSCLC should also have
received targeted therapies.
Exclusion criteria
All Patients:
1. Intervention with any of the following
• Any chemotherapy, investigational agents or other anti-cancer drugs within 14
days or 5 half-lives (whichever is longer of these two) of the first dose of
study treatment (excludes treatment with immunotherapy agents which must be
assessed on a case by case basis). This does not apply to prior treatment with
abiraterone for patients in Part C1 or C2 or prior treatment with enzalutamide
for patients in Part D1 (except patients in the DDI arm who must have a 4 week
washout of enzalutamide prior to starting the study) and D2.
• Radiotherapy with a wide field of radiation or to more than 30% of the bone
marrow within 4 weeks of the first dose of study treatment
• Major surgical procedure or significant traumatic injury as judged by the
investigator, within 4 weeks of the first dose of study treatment, or have an
anticipated need for major surgery during the study
• Strong inducers of CYP3A4 (See Appendix E) taken within 4 weeks of the first
dose of study treatment or while on study treatment (excluding enzalutamide in
Part D1 and D2 which does not require a 4 week wash-out prior to the first dose
of study treatment, except for patients in the DDI arm).
• Strong inhibitors of CYP3A4 or CYP2C8 or CYP3A4 sensitive substrates (See
Appendix E) taken within 2 weeks of the first dose of study treatment or while
on study treatment.
• Washout periods may be reduced for specific medications (eg. statins)
following discussion with the medical monitor.
• Herbal medications cannot be taken within 7 days of the first dose of study
treatment (4 weeks for St John*s wort) or while on study treatment
• Statins; patients may receive fluvastatin or pravastatin (with monitoring for
potential toxicities), or atorvastatin or simvastatin at 10mg daily dose only.
Patients
• Systemic cancer treatment should not be initiated for at least 30 days after
the last administration of Radium-223 (Ra-223, Xofigo)
2. Any unresolved reversible toxicities from prior therapy greater than Common
Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting
study treatment with the exception of alopecia and neuropathy
3. Female patients who are pregnant or breast-feeding at study entry. Breast
feeding is contraindicated during study treatment and for 1 month after study
drug is discontinued.
4. Any evidence of severe or uncontrolled systemic diseases, including for
example diabetes, uncontrolled hypertension and active bleeding diatheses,
which in the investigator*s opinion makes it undesirable for the patient to
participate in the study or which would jeopardise compliance with the
protocol, or active infection* including hepatitis B, hepatitis C and human
immunodeficiency virus (HIV). *Active viral infection is defined as requiring
antiviral therapy. Screening for chronic conditions is not required
5. Patients with any known uncontrolled inter-current illness including ongoing
or active clinically significant infections, symptomatic congestive heart
failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements. Refractory nausea and vomiting, chronic gastrointestinal diseases
or previous significant bowel resection, with clinically significant sequelae
that would preclude adequate absorption of study treatments
6. Repeatable QTcF prolongation (>480 msec)
7. Prior malignancy that could affect compliance with the protocol or
interpretation of results. Patients with a history of non-melanoma skin cancers
or carcinoma in situ treated with curative intent, are generally eligible
8. Primary brain tumours or known or suspected brain metastases. Patients with
brain metastases could be eligible if treated and stable within 28 days of the
first dose of study treatment (after discussion and agreement with the
CellCentric medical advisor).
9. Patients with any known severe allergies to any active or inactive
ingredients in the study medications
Additional exclusion criteria for patients in CCS1477 plus abiraterone
combination arm (Part C)
10. Patients with clinically significant cardiac abnormalities or
contraindications to abiraterone such as:
Severe hepatic impairment (Child-Pugh class C)
11. Clinically significant cardiac abnormalities as assessed by the treating
physician that may include (but not be limited to) recent myocardial infarction
(<=6 months) or unstable angina (<=3 months), New York Heart association (NYHA)
class III or IV heart failure except if LVEF is >=50%, clinically significant
uncontrolled rhythm disturbances, and patients with uncontrolled hypertension
Note: Abiraterone is contraindicated in combination with Radium-223
Additional exclusion criteria for patients in CCS1477 plus enzalutamide
combination arm (Part D)
12. History of seizures or other predisposing factors including, but not
limited to, underlying brain injury, stroke, primary brain tumours, brain
metastases and leptomeningeal disease, or alcoholism
13. Use of substrates with a narrow therapeutic index metabolised by CYP2C9 or
CYP2C19 within 2 weeks of the first dose of study treatment
14. Patients with clinically significant cardiac abnormalities as assessed by
the treating physician that may include (but not be limited to) recent
myocardial infarction (<=6 months) or unstable angina (<=3 months), New York
Heart association (NYHA) class III or IV heart failure except if LVEF is >=50%,
clinically significant uncontrolled rhythm disturbances, and patients with
uncontrolled hypertension
Additional exclusion criteria for patients in CCS1477 plus darolutamide
combination (Part F)
15. The use of moderate CYP3A4 inducers taken within 4 weeks of the first dose
of study treatment or while on study treatment
16. Patients with rare hereditary problems of galactose intolerance, total
lactase deficiency or glucose-galactose malabsorption
Additional exclusion criteria for patients in CCS1477 plus olaparib combination
(Part G)
17. Severe hepatic impairment (Child-Pugh class C)
18. The use of moderate inhibitors of CYP3A4 taken within 2 weeks of the first
dose of study treatment or while on study treatment
19. Evidence of MDS/AML on peripheral blood smear
Additional exclusion criteria for patients in CCS1477 plus atezolizumab
combination (Part H)
20. History of autoimmune disease, including, but not limited to myasthenia
gravis, myositis, pneumonitis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular
thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis,
Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or
glomerulonephritis. Subjects with diabetes mellitus type I, hypothyroidism only
requiring hormone replacement or controlled hyperthyroidism, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are
permitted to enrol.
21. Patients administered a live, attenuated vaccine within 28 days prior to
first dose; systemic immunostimulatory agents within 4 weeks or 5 half lives
(whichever is longer), or systemic immunosuppressive medicinal products within
2 weeks prior to first dose of study treatment.
22. Active tuberculosis
23. Severe infection within 4 weeks, or IV antibiotics treatment within 2 weeks
of the first dose of study treatment
24. Prior allogeneic bone marrow or solid organ transplant
25. Treatment with systemic corticosteroids (>10mg daily of prednisolone or
equivalent) within 1 week of the first dose of study treatment
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 | EUCTR2018-000285-10-NL |
| ClinicalTrials.gov | NCT03568656 |
| CCMO | NL77469.056.21 |