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JOURNAL ONKOLOGIE – STUDIE

Open-label Dose Escalation Phase 1b Trial of a New Micellar Docetaxel Compound in Patients With mCRPC

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NCT-Nummer:
NCT04629781

Studienbeginn:
März 2021

Letztes Update:
16.11.2020

Wirkstoff:
Docetaxel micellar

Indikation (Clinical Trials):
Prostatic Neoplasms

Geschlecht:
Männer

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Swiss Group for Clinical Cancer Research

Collaborator:
-

Studienleiter

Ilaria Colombo, MD
Study Chair
IOSI, Ospedale San Giovanni, Bellinzona

Kontakt

Studienlocations (3 von 3)

Studien-Informationen

Detailed Description:

Docetaxel, a semi-synthetic analogue of paclitaxel, is one of the most widely used human

anti-cancer agents. Docetaxel and paclitaxel belong to a group of cytotoxic agents called

taxanes. Docetaxel has been marketed worldwide by Sanofi-Aventis under the trade name

Taxotere® and its use is approved for different types of solid tumors. The efficacy of

docetaxel has been proven in two different phase 3 trials in metastatic castration resistant

prostate cancer (mCRPC) and is a standard of care option for patients with prostate cancer.

In Taxotere®, polysorbate 80 is used as surfactant. Fluid retention and hypersensitivity

reactions are reported, and the patients are pre-treated with corticosteroids, e.g.

dexamethasone, to avoid or at least reduce the frequency and the severity of both

hypersensitivity reactions and fluid retention.

Oasmia Pharmaceutical AB (Uppsala, Sweden) has developed a novel formulation of docetaxel

(Docetaxel micellar) with N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt

(XMeNa) as excipient, thus reducing adverse reactions caused by polysorbate 80. XMeNa forms

micelles into which docetaxel can be incorporated thus increasing its aqueous solubility and

keeping it dissolved.

Rational Treatment with polysorbate 80-solved Docetaxel (Taxotere) is hampered by the

requirement to co-administer steroid pre and post Taxotere infusion. Chronic (intermittent)

steroids are hurting bone health and have well known immunosuppressive effects. Despite

steroid premedication, polysorbate 80-solved Docetaxel (Taxotere) results in occasional

infusion reactions due to the solvent polysorbate 80. The new micellar formulation of

docetaxel is a promising alternative to polysorbate 80-solved Docetaxel (Taxotere) as it

avoids the mandatory need for steroid administration pre and post infusion, and thus avoids

immunosuppressive and bone-damaging effects.

Safety and pharmacokinetics (PK) of Docetaxel micellar have been assessed in 2 clinical

studies, but only in breast cancer patients. This is the first clinical trial to assess the

safety and tolerability of 3-weekly intravenous Docetaxel micellar infusions in patients with

mCRPC.

The primary objective of this study is to determine the maximum tolerated dose (MTD) and the

recommended phase II dose (RP2D) for Docetaxel micellar in patients with mCRPC.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Written informed consent according to Swiss law and ICH GCP E6(R2) regulations before

registration and prior to any trial specific procedures.

- Histologically confirmed adenocarcinoma of the prostate

- Metastatic castration resistant, progressive disease as defined as per PCWG3 criteria

- Ongoing concurrent use of GnRH agonist or antagonist is required if the patient has

not been surgically castrated

- Measurable or evaluable disease per Recist 1.1 and as per PCWG3

- Patients with treated and stable CNS metastases are eligible, provided they meet the

following criteria:

- No ongoing requirement for corticosteroids as therapy for symptomatic CNS

disease; anticonvulsants at a stable dose allowed

- No stereotactic radiation or whole-brain radiation within 7 days prior to

registration,

- No evidence of progression for at least 4 weeks after completion of CNS-directed

therapy as verified by clinical examination and brain imaging (MRI or CT) during

the screening period

- Patients with a previously treated malignancy are eligible, when the risk of the prior

malignancy interfering with either safety or efficacy endpoints is very low.

- Age ≥ 18 years

- ECOG performance status 0-1

- Adequate bone marrow function: (patient must not have received any growth factor or

blood transfusion within 7 days prior to registration): neutrophil count ≥ 1.5 x 109/L

, platelet count ≥ 100 x 109/L, hemoglobin ≥ 80 g/L

- Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with

Gilbert's disease 3.0 x ULN), AST and ALT ≤ 2.5 x ULN

- Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73

m2 (according to CKD-EPI formula)

- Willingness to have a central venous line inserted (PICC or Porth-a-Cath) if not

already present.

- Men agree not to donate sperm or to father a child during trial treatment and until 6

months after the last dose of investigational drug. Sexually active patients must

agree to have an effective contraception during study treatment and for 6 months after

the last dose.

Exclusion Criteria:

- Clinical or radiological evidence of spinal cord compression

- Known predominant small cell or neuroendocrine component on histological diagnosis

- Prior chemotherapy including docetaxel for the treatment of prostate cancer (previous

administration of chemotherapy concomitant with ADT is not allowed )

- Prior use of taxane-based chemotherapy for any other previous cancer

- Prior systemic treatment, immunotherapy, hormonal therapy (with the exception of GnRH

agonists or antagonists) or investigational agents within 21 days before registration,

with the exception of palliative radiotherapy (within 2 weeks)

- Concomitant or within 28 days of registration treatment with any other experimental

drug (enrollment in another clinical trial except participation in SAKK 96/12 and/or

63/12]

- Concomitant use of other anti-cancer drugs (other than GnRH agonists or antagonists).

Bone-modifying agents (such as bisphosphonates or denosumab) are allowed before study

entry and during treatment.

- Patients who have not recovered to CTCAE grade ≤1 from clinically relevant adverse

events of prior therapies, except for residual toxicities, such as alopecia, which do

not pose an ongoing medical risk.

- Peripheral neuropathy > CTCAE grade 1

- Localized or general edema > CTCAE grade 1

- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or

IV; unstable angina pectoris, history of myocardial infarction within the last six

months, serious arrhythmias requiring medication (with exception of atrial

fibrillation or paroxysmal supraventricular tachycardia), known significant

QT-prolongation, uncontrolled hypertension.

- Major surgery within 4 weeks prior to registration

- Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or

Hepatitis B Virus infection or any uncontrolled active systemic infection requiring

intravenous (iv) antimicrobial treatment.

- Concomitant or prior use of immunosuppressive medication within 28 days before

registration, with the exceptions of intranasal and inhaled corticosteroids, or

systemic corticosteroids which must not exceed 10 mg/day of prednisone or a dose

equivalent corticosteroid)

- Concomitant treatment with strong CYP3A inducers or inhibitors

- Any concomitant drugs contraindicated for use with the trial drugs according to the

approved product information

- Known hypersensitivity to trial drug(s) or to any component of the trial drug(s)

- Any other serious underlying medical, psychiatric, psychological, familial or

geographical condition, which in the judgment of the investigator may interfere with

the planned staging, treatment and follow-up, affect patient compliance or place the

patient at high risk from treatment-related complications.

Studien-Rationale

Primary outcome:

1. Dose-limiting toxicity (DLT) (Time Frame - at the end of Cycle 1 (each cycle is 21 days)):
DLT is defined as the occurrence of any of a set of specified hematological, hepatic, gastro-intestinal, nervous systems disorders, fluid retention or other adverse events (AEs) which: occur during cycle 1 of the trial treatment defined as the DLT monitoring period is considered by the Investigator or the Sponsor to be at least possibly related to the IMP.



Secondary outcome:

1. Radiographic progression-free survival (rPFS) (Time Frame - from date of treatment start to date of radiographic progression, or death due to any cause, whichever occurs first, assessed up to 36 months):
rPFS is defined as the time from treatment start to radiographic progression, or death due to any cause, whichever occurs first. The assessment of radiographic disease progression is based on local evaluations.

2. Time to PSA progression (Time Frame - from date of treatment start to date of PSA progression, or start of a subsequent anticancer treatment, whichever occurs first, assessed up to 36 months):
Time to PSA progression is defined as the time from treatment start to the time point of PSA progression. The PSA progression date is defined as the date of ≥ 25% increase AND ≥ 2 ng/mL increase above the nadir, confirmed by a second value ≥ 3 weeks later, if there is PSA decline from baseline (last PSA measurement before treatment start), or ≥ 25% increase AND ≥ 2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline Time to PSA progression is defined as the time from treatment start to the time point of PSA progression. The PSA progression date is defined as the date of ≥ 25% increase AND ≥ 2 ng/mL increase above the nadir, confirmed by a second value ≥ 3 weeks later, if there is PSA decline from baseline (last PSA measurement before treatment start), or ≥ 25% increase AND ≥ 2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline

3. PSA response (Time Frame - from date of treatment start to date of end of treatment, assessed up to 30 weeks):
PSA response is defined as a PSA decline of ≥ 50% from baseline measured twice at least 3 weeks apart during treatment.

4. Partial (PR) or complete (CR) radiological soft tissue response according to RECIST 1.1 (Time Frame - from date of treatment start to date of end of treatment, assessed up to 30 weeks):
Partial (PR) or complete (CR) radiological soft tissue response achieved according to RECIST 1.1 criteria. Patients without any response assessment during trial treatment will be considered as having a non-evaluable response (NE) and thus will be regarded as failure for this endpoint.

5. Duration of response (DoR) according to RECIST 1.1 (Time Frame - from date of response to date of disease progression according to RECIST 1.1 or death, whichever occurs first, assessed up to 36 months):
DoR is defined as the time from the earliest date of the first documented evidence of complete response (CR) or partial response (PR) until earliest date of disease progression according to RECIST 1.1 or death due to any cause, whichever occurs first. Patients not experiencing an event at the time of the analysis, as well as patients starting a subsequent anticancer treatment in the absence of an event, will be censored at the date of their last available tumor assessment before starting a subsequent anticancer treatment, if any.

6. Adverse Events (Time Frame - From registration until 28 days after last dose of trial treatment):
AEs will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Geprüfte Regime

  • Docetaxel micellar:
    There will be three dose levels, 1-3, with each level consisting initially of a cohort containing 3 patients. One additional dose level, dose level -1, shall be allowed in the event that dose level 1 is considered too toxic

Quelle: ClinicalTrials.gov


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