Primary objective: To evaluate the safety, tolerability, and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of investigational therapies in subjects with metastatic castration-resistant prostate cancer (mCRPC).Secondary objective:*…
ID
Source
Brief title
Condition
- Other condition
- Prostatic disorders (excl infections and inflammations)
Synonym
Health condition
prostaat kanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The following primary study outcome is applicable for both combination
therapies:
To evaluate the safety, tolerability, and maximum tolerated dose (MTD) or
recommended phase 2 dose (RP2D) of AMG 160 in combination with enzalutamide or
abiraterone in subjects with metastatic castration-resistant prostate cancer
(mCRPC)
* dose-limiting toxicities (DLTs)
* treatment-emergent and treatment-related adverse events
* changes in vital signs and clinical laboratory tests
Secondary outcome
The following secundary study outcome is applicable for both combination
therapies:
To evaluate preliminary anti-tumor activity of AMG 160 in combination with
enzalutamide or abiraterone
* objective response per Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 with Prostate Cancer Working Group 3 (PCWG3) modifications
* circulating tumor cell (CTC) response (CTC0 and CTC conversion)
* prostate-specific antigen (PSA) response
* duration of response (CTC, PSA, conventional radiographic)
* overall survival (OS)
* progression-free survival (radiographic, PSA, clinical)
* time to progression (radiographic, PSA)
* time to subsequent therapy
* 68Gallium (68Ga)-prostate-specific membrane antigen (PSMA)-11 positron
emission tomography (PET)/computed tomography (CT) and 18F-fluorodeoxyglucose
(FDG) PET/CT based response evaluation
* other PCWG3-recommended endpoints (time to symptomatic skeletal events,
alkaline phosphatase [total, bone], lactate dehydrogenase [LDH], hemoglobin,
neutrophil to-lymphocyte ratio, urine N-telopeptide)
To characterize the pharmacokinetics (PK) of AMG 160 in combination with
enzalutamide or abiraterone
* PK parameters including, but not limited to, maximum serum concentration
(Cmax), minimum serum concentration (Cmin), area under the concentration-time
curve (AUC) over the dosing interval, accumulation, and half-life (t1/2)
Background summary
AMG160 is a new half-life extended (HLE) bispecifiic T-cell engager (BiTE®)
molecule designed to target T-effector cells to prostate-specific membrane
antigen (PSMA) expressing cells.
Disease relapse following enzalutamide / abiraterone is due in part to
increased androgen receptor expression (eg. androgen receptor amplification),
among other mechanisms. Because these resistance mechanisms do not necessarily
confer resistance to immunotherapies like AMG 160, there is a rationale to
combine enzalutamide / abiraterone with AMG 160. Furthermore, NHT like
enzalutamide or abiraterone have been reported to upregulate PSMA expression on
castration-resistant prostate cancer cells, providing additional rationale to
combine with PSMA targeted therapies like AMG 160.
This study will evaluate the safety, tolerability and preliminary efficacy of
AMG 160 in combination with enzalutamide or abiraterone in subjects with mCRPC.
See section 2.1 in sub protocol A and B for further details.
Study objective
Primary objective:
To evaluate the safety, tolerability, and maximum tolerated dose (MTD) or
recommended phase 2 dose (RP2D) of investigational therapies in subjects with
metastatic castration-resistant prostate cancer (mCRPC).
Secondary objective:
*To evaluate preliminary anti-tumor activity of investigational therapies in
subjects with mCRPC
*To characterize the pharmacokinetics (PK) of investigational therapies in
subjects with mCRPC
Study design
Overall study design for both combination therapies:
This is a phase 1b, multicenter, open-label study evaluating the safety,
tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 160
in combination with enzalutamide or abiraterone. The study will consist of dose
exploration (Part 1) and dose expansion (Part 2).
Subjects will be treated until progression (treatment beyond disease
progression may be allowed per Prostate Cancer Working Group 3 [PCWG3]
guidelines if approved by Amgen medical monitor). Upon permanent
discontinuation from the study treatment for any reason, a safety follow-up
visit will be performed approximately 30 (+3) days after the last dose of
protocol-required therapy or prior to initiation of subsequent therapy,
whichever occurs first. After the safety follow-up visit, subjects enter
long-term follow-up to assess survival and/or the initiation of subsequent
cancer therapy. Long-term follow-up will be conducted every 6 months after the
last dose of protocol-required therapy up to 3 years from cycle 1 day 1.
Part 1 (Dose Exploration):
The dose exploration part of the study will estimate the maximum tolerated dose
(MTD)/recommended phase 2 dose (RP2D) of AMG 160 in combination with
enzalutamide or abiraterone using a modified toxicity probability interval
(mTPI) design. A RP2D may be identified based on emerging safety, efficacy, and
pharmacodynamic data prior to reaching an MTD.
Part 2 (Dose Expansion):
Upon completion of Part 1 of the study, enrollment will commence in Part 2 to
confirm the safety and tolerability of the selected dosing regimen and to
further evaluate the efficacy of AMG 160 in combination with enzalutamide or
abiraterone.
Intervention
Dispension of IP:
Subprotocol A: AMG 160 in combination with enzalutamide
Based on Study 20180101, the AMG 160 starting dose for this study will be
0.09/0.3 mg (MTD/RP2D). This would mean that 0.09 mg of AMG 160 will be
administered on cycle 1 day 1 as a 3-day extended IV infusion followed by 0.3
mg maintenance dose starting cycle 1 day 8 and Q2W via short-term infusion.
Enzalutamide (160 mg) should be taken once daily.
Depending on observed safety data, the following may occur: additional
enrollment to above mentioned dose; or dose de-escalation to 1 dose level below
MTD / RP2D of AMG 160 (ie. 0.15 mg). De exploration phase is further explained
in 6.2.1.1 of subprotocol A.
Following dose exploration, dose-expansion will be conducted to confirm the
safety and tolerability of the selected dose and to further evaluate the
efficacy of AMG 160 in combination with enzalutamide.
Subprotocol B: AMG 160 in combination with abiraterone
Based on Study 20180101, the AMG 160 starting dose for this study will be
0.09/0.15 mg (1 dose level below MTD/RP2D). This would mean that 0.09 mg of AMG
160 will be administered on cycle 1 day 1 as a 3-day extended IV infusion
followed by 0.15 mg maintenance dose starting cycle 1 day 8 and Q2W via
short-term infusion. Abiraterone (1000 mg) should be taken once daily.
Depending on observed safety data, the following may occur: additional
enrollment to above mentioned dose (1 dose level below MTD/RP2D); or dose
de-escalation to 2 dose level below MTD / RP2D of AMG 160 (ie, 0.09 mg); or
dose escalation to MTD / RP2D of AMG 160 (ie. 0.3 mg) De exploration phase is
further explained in 6.2.1.1 of subprotocol B.
Following dose exploration, dose-expansion will be conducted to confirm the
safety and tolerability of the selected dose and to further evaluate the
efficacy of AMG 160 in combination with abiraterone.
Study burden and risks
Next to the key safety risks;
* Cytokine release syndrome (CRS),
* Gastrointestinal toxicities,
* Neurologic toxicities,
* Tumor lysis syndrome,
* Supraventricular arrythmias (related to CRS),
* Thrombocytopenia (related to CRS),
* Eye disorders,
the following should be taken into account in terms of burden to the patient:
* Blood draw: Drawing blood may be painful or cause some bruising.
* Exposure to radiation: CT scan, PET, MUGA and the bone scan involves using
X-rays or radioactive markers.
Please refer to Appendix D in ICF for more information about possible side
effects, risks, complications and other undesirable effects for all tests and
procedures performed in this study.
Disadvantages of participation in the study may be:
- Possible side effects/complications
- Possible adverse effects/discomforts of the evaluations in this study.
Participation in the study also means:
- additional time
- additional or longer hospital stays
- additional tests
- instructions you need to follow.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
- Subject has provided informed consent prior to initiation of any study
specific activities/procedures.
- Age * 18 years at the time of signing the informed consent.
- Subjects with mCRPC with histologically or cytologically confirmed
adenocarcinoma of the prostate without pure neuroendocrine differentiation or
small cell features.
- Subjects should have undergone bilateral orchiectomy or should be on
continuous androgen deprivation therapy with a gonadotropin releasing hormone
agonist or antagonist.
- Total serum testosterone should be * 50 ng/dL (or 1.7 nmol/L)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 * 1
- Life expectancy of > 3 months
- Adequate organ function, defined as follows:
* absolute neutrophil count * 1.5 x 10^9/L (without growth factor support
within 7 days from screening assessment)
* platelet count * 100 x 10^9/L (without platelet transfusion within 7 days
from screening assessment)
* hemoglobin > 9 g/dL (90 g/L) (subprotocol A) / > 10 g/dL (100g/L)
(subprotocol B) (without blood transfusion within 7 days from screening
assessment)
* estimated glomerular filtration rate based on Modification of Diet in Renal
Disease (MDRD) calculation * 30 mL/min/1.73 m2
* AST and ALT < 3 x upper limit of normal (ULN) (or < 5 x ULN for subjects with
liver involvement)
* total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for subjects with liver
metastases)
* left ventricular ejection fraction (LVEF) > 50% (2-D transthoracic
echocardiogram [ECHO] is the preferred method of evaluation; multi-gated
acquisition scan is acceptable if ECHO is not available)
- Baseline electrocardiogram (ECG) QTc * 470 msec
- Subjects planning to receive enzalutamide (subprotocol A) / abiraterone
(subprotocol B) for the first time for mCRPC (subjects who received prior
enzalutamide (subprotocol A) / abiraterone (subprotocol B) are not eligible).
Exclusion criteria
Applicable for both subprotocols:
- Pathological finding consistent with pure small cell, neuroendocrine
carcinoma of the prostate or any other histology different from adenocarcinoma
- CNS metastases or leptomeningeal disease
- Symptomatic peripheral sensory or motor neuropathy *grade 3
- History or presence of clinically relevant CNS pathology
- Confirmed history/current autoimmune disease or other diseases resulting in
permanent immunosuppression or requiring permanent immunosuppressive therapy
- Presence of fungal, bacterial, viral, or other infection requiring IV
antimicrobials within 7 days of dosing
- History/evidence of inflammatory bowel disease or any other gastrointestinal
disorder causing chronic nausea, vomiting, or diarrhea
- History of arterial or venous thrombosis within 12 months of first dose
- Myocardial infarction, uncontrolled hypertension (Subprotocol A), unstable
angina, cardiac arrhythmia requiring medication, and/or symptomatic congestive
heart failure (New York Heart Association > class II) within 12 months of first
dose of AMG 160
- Unresolved toxicities from prior anti-tumor therapy not having resolved to
CTCAE version 5.0 grade 1, with the exception of alopecia or toxicities that
are stable and well-controlled AND there is agreement to allow by both the
investigator and sponsor
- Known HIV infection, hepatitis C or hepatitis B infection
- History of other malignancy within the past 2 years, with the following
exceptions:
* Malignancy treated with curative intent and with no known active disease
present for * 3 years before enrollment and felt to be at low risk for
recurrence by the treating physician.
* Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease.
* Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in
situ.
- Prior treatment with a taxane for mCRPC.
- Radiation therapy within 4 weeks of first dose (or local or focal
radiotherapy within 2 weeks)
- Any anticancer therapy or immunotherapy within 4 weeks of start of first
dose, not including LHRH/GnRH analogue. Subjects on a stable bisphosphonate or
denosumab regimen for * 30 days prior to enrollment are eligible
- Prior PSMAxCD3 bispecific therapy
- Requiring chronic systemic corticosteroid therapy or any other
immunosuppressive therapies. Low dose corticosteroids permitted.
- Prior major surgery within 4 weeks of first dose
- Currently receiving treatment in another investigational device or drug
study, or less than 4 weeks since ending treatment on another investigational
device or drug study(ies).
- Male subjects with a female partner of childbearing potential or pregnant
partner who are unwilling to practice sexual abstinence or use contraception
during treatment and for an additional 4 months after the last dose
- Male subjects unwilling to abstain from donating sperm during treatment and
for an additional 4 months after the last dose.
- Subject has known sensitivity to any of the products (or components) to be
administered during dosing.
- Subject likely to not be available to complete all protocol-required study
visits or procedures, and/or to comply with all required study procedures.
Subprotocol A
- Use of strong CYP2C8 inhibitors within 7 days prior to first dose or strong
CYP3A4 inducers within 28 days
- Use of narrow therapeutic index drugs that are substrates of CYP3A4, CYP2C9
or CYP2C19 within 28 days.
Subprotocol B
- Baseline moderate and severe hepatic impairment
- Presence of uncontrolled hypertension, hypokalemia, or fluid retention
- History or presence of adrenocortical insufficiency
- Use of concomitant medications that are sensitive substrates for CYP2D6 with
a narrow therapeutic index within 7 days
- Use of strong CYP3A4 inducers within 28 days.
Please refer to section 5.2 of subprotocol A and B for the complete list of
exclusion criteria.
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 | EUCTR2020-001305-23-NL |
| ClinicalTrials.gov | NCT04631601 |
| CCMO | NL74207.056.20 |