BADANIA KLINICZNE PROWADZONE W POLSCE

BK 1 fazy Niraparib+ABI podawane w różnych sekwencjach w mCR

Nieprzeczytany postautor: zosia bluszcz » 23 kwie 2021, 02:42

An Open-label, Randomized Study to Assess the Relative Bioavailability (BA) and Bioequivalence (BE) of Comparative Formulations of Niraparib and Abiraterone Acetate (AA) in Men With Prostate Cancer


Detailed Description:
Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases.
AA is a pro-drug of abiraterone which selectively inhibits the enzyme 17 alpha-hydroxylase/C17,20-lyase (CYP17), that is found in the testes and adrenals (leading to systemic inhibition of testosterone production), as well as in prostate tissues and tumors.

The rationale of the study is to investigate the various strengths and formulations of niraparib and AA plus prednisone or prednisolone (P) in metastatic castration resistant prostate cancer (mCRPC) participants with and without homologous recombination repair (HRR) gene alterations.
In participants with metastatic prostate cancer, DNA-repair anomalies are found in approximately 15 percent (%) to 20% of tumors.

This study consists 4 periods:
=> screening phase (up to 21 days);
=> treatment phase (up to 22 days);
=> extension phase (from day 23 until discontinuation);
=> and post-treatment follow up phase (end of treatment [EoT] visit within 30 days after the last dose of study treatment).
Total duration of study is up to 1.4 years.
Efficacy, safety, pharmacokinetics (PK), and biomarkers will be assessed at specified time points during this study. Participants safety will be monitored throughout the study.


Criteria

Inclusion Criteria:

=> Histologically or cytologically confirmed adenocarcinoma of the prostate
=> Diagnosed with metastatic castration-resistant prostate cancer (mCRPC), who in the opinion of the investigator may benefit from treatment in this study
=> Able to continue gonadotropin-releasing hormone analogues (GnRHa) therapy during the study if not surgically castrate (that is, participants who have not undergone bilateral orchiectomy)
=> Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1
=> Willing to provide a tumor sample (archival) for determination of homologous recombination repair (HRR) gene alteration status


Exclusion Criteria:

=> Symptomatic brain metastases
=> Prior disease progression during treatment with abiraterone acetate (AA) alone or when combined with a poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi). Prior discontinuation of treatment with AA or PARPi due to AA- or PARPi related toxicity.
=> History or current diagnosis of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML)
=> Known allergies, hypersensitivity, or intolerance to niraparib or AA or the corresponding excipients of niraparib/AA
=> Any medical condition that would make prednisone/prednisolone use contraindicated



Poland

Uniwersyteckie Centrum Kliniczne Recruiting
Gdansk, Poland, 80-214

Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy Recruiting
Warszawa, Poland, 02-781


https://clinicaltrials.gov/ct2/show/NCT04577833
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BK fazy 1/2 MGC018 + Retifanlimab (MGA012) w mCRPC (m.in.)

Nieprzeczytany postautor: zosia bluszcz » 23 kwie 2021, 03:02

A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of MGC018 (Anti-B7-H3 Antibody Drug Conjugate) Alone and in Combination With MGA012 (Anti-PD-1 Antibody) in Patients With Advanced Solid Tumors


Brief Summary:
The purpose of this study is to evaluate the safety and tolerability, pharmacokinetics (PK) pharmacodynamics and preliminary antitumor activity of MGC018 administered alone and in combination with MGA012 in patients with advanced solid tumors


Detailed Description:
This Phase 1/2 study will characterize safety, dose-limiting toxicities (DLTs), and maximum tolerated/administered dose (MTD/MAD) and anti-tumor activity for MGC018 as monotherapy (Module A) in patients with advanced solid tumors.
Each module consists of a Dose Escalation (3+3+3 design) followed by a Cohort Expansion Phase. Patients with solid tumors will be enrolled in the Dose Escalation Phase;
Cohort Expansion will include metastatic castrate-resistant prostate cancer (mCRPC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma.
Patients who do not experience unacceptable toxicity or meet criteria for permanent discontinuation may undergo additional cycles for up to two years.
Patients in Cohort Expansion will be followed for survival every 3 months for 2 years following last dose.


Module B, MGC018 in combination with MGA012, Dose Escalation and Cohort Expansion will commence only upon sponsor notification to all study investigators.


Criteria

Inclusion Criteria:

=> Tissue specimen available for retrospective analysis of B7-H3 and PD-L1 expression.
=> Eastern Cooperative Oncology Group performance status of ≤2
=> Life expectancy ≥ 12 weeks for dose escalation phase and ≥ 24 weeks for cohort expansion phase
=> Measurable disease. Prostate cancer patients with bone only disease are eligible.
=> Acceptable laboratory parameters and adequate organ reserve.

Dose Escalation Phase:
Patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no therapy with demonstrated clinical benefit is available.

Module A Cohort Expansion:
=> mCRPC that has progressed with one prior line of chemotherapy for metastatic disease and no more than two prior lines of anti-hormonal therapy.
(...)


Exclusion Criteria:

=> Patients with history of prior central nervous system (CNS) metastasis must have been treated, be asymptomatic, and not have concurrent treatment for CNS disease, progression of CNS metastases on MRI, CT or PET within 6 months, or history of leptomeningeal disease or cord compression at the time of enrolment.
=> Prior treatment with B7-H3 targeted agents for cancer.
=> Treatment with systemic cancer therapy, biologic agents, or anti-hormonal therapy (mCRPC) within 4 weeks, prior small molecule targeted or kinase inhibitors within 14 days or 5 half-lives, prior radioligand within 6 months
=> Clinically significant cardiovascular disease.
=> Clinically significant pulmonary compromise or requirement for supplemental oxygen.
=> History of clinically-significant cardiovascular disease, including but not limited to pericarditis or pericardial effusion.
=> Active viral (including confirmed or presumed COVID-19), bacterial, or systemic fungal infection requiring parenteral treatment within 7 days of first study drug administration.
=> Known history of hepatitis B or C infection or known positive test for hepatitis B surface antigen or core antigen, or hepatitis C polymerase chain reaction.
=> Known positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome.
=> Major trauma or major surgery within 4 weeks of first study drug administration.
=> Clinically significant venous insufficiency.
=> > Grade 1 peripheral neuropathy.
=> Evidence of pleural effusion.
=> Evidence of ascites.
=> Serum testosterone >50 ng/dl or >1.7 nmol/L in mCRPC in Module A Cohort Expansion Phase


Poland

Samodzielny Publiczny Zakład Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie Oddział Kliniczny Onkologii Recruiting
Krakow, Poland, 31-501
Contact: Piotr Wysocki 48 12 424 89 12 piotr.wysocki@uj.edu.pl
Principal Investigator: Piotr Wysocki

Med-Polonia Sp. z o.o. Recruiting
Poznań, Poland, 60-693
Contact: Rodryg Ramlau 48505758992 rramlau@gmail.com
Principal Investigator: Rodryg Ramlau

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie Państwowy Instytut Badawczy Oddział Badań Wczesnych Faz Recruiting
Warsaw, Poland, 02-781
Contact: Joanna Dylewska-Rzeznik 48 22 546 26 94 Joanna.Dylewska-Rzeznik@pib-nio.pl
Principal Investigator: Iwona Lugowska

Magodent Sp. z o.o. Szpital Elbląska Oddział Onkologii Klinicznej/ Chemioterapii Recruiting
Warszawa, Poland, 01-748
Contact: Jakub Żołnierek 48 22 430 88 50 qbazolnier@wp.pl
Principal Investigator: Jakub Żołnierek


https://clinicaltrials.gov/ct2/show/NCT03729596





Retifanlimab (previously known as MGA012) is an investigational, humanized, proprietary anti-PD-1 monoclonal antibody being developed for use as monotherapy as well as in combination with other potential cancer therapeutics. Retifanlimab was licensed to Incyte Corporation in 2017 under a global collaboration and license agreement
https://www.macrogenics.com/mga012-pd-1/




MGC018 (B7-H3)
MGC018 is an investigational antibody-drug conjugate (ADC) comprised of a humanized B7-H3 monoclonal antibody (mAb) conjugated via a cleavable linker to the prodrug seco-DUocarmycin hydroxyBenzamide Azaindole (DUBA; licensed from Byondis, B.V.), with an average drug-to-antibody ratio (DAR) of ~2.7. DUBA is an alkylating agent that can damage DNA in both dividing and non-dividing cells, causing cell death. MGC018 is designed to target solid tumors expressing B7-H3.

https://www.macrogenics.com/mgc018-b7-h3/




Incyte Announces the Validation by the European Medicines Agency of its Marketing Authorization Application for Retifanlimab as a Treatment for Patients with Squamous Cell Anal Carcinoma (SCAC)
https://www.businesswire.com/news/home/ ... inoma-SCAC

FDA Grants Priority Review for Retifanlimab for Advanced Squamous Cell Carcinoma of the Anal Canal
https://www.targetedonc.com/view/fda-gr ... anal-canal
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Cabozatinib+Atezolizumab vs Second NHT (ABI/ENZ) in mCRPC

Nieprzeczytany postautor: zosia bluszcz » 07 wrz 2021, 11:00

A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination With Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects With Metastatic Castration-Resistant Prostate Cancer NCT04446117

Experimental: Experimental Arm
Subjects with mCRPC will receive cabozantinib 40mg oral, qd + atezolizumab 1200mg infusion, q3w

Active Comparator: Control Arm
Subjects with mCRPC will receive active comparator of EITHER abiraterone 1000mg oral, qd + prednisone 5 mg oral, bid; OR enzalutamide 160mg oral, qd as designated by the Investigator prior to randomisation



Criteria

Inclusion Criteria:
=> Men with histologically or cytologically confirmed adenocarcinoma of the prostate
=> Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or mCSPC, M0 CRPC, or mCRPC
=> Surgical or medical castration, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening
=> Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment defined by at least one of the following: measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen) per RECIST 1.1; OR measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation)
=> Progressive disease at study entry as defined by specific criteria for prostate specific antigen (PSA) progression OR soft tissue disease progression in the opinion of the Investigator (Note: subjects with bone disease progression alone are not eligible)
(...)
=> ECOG performance status of 0 or 1
=> Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator
=> Adequate organ and marrow function based upon specific laboratory assessments obtained within 21 days prior to randomization
=> Understanding and ability to comply with protocol requirements


Exclusion Criteria:
=> Any prior nonhormonal therapy initiated for the treatment of mCRPC
=> Receipt of abiraterone within 1 week; cyproterone within 10 days; or flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks before randomization
=> Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization (subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible)
=> Known brain metastases or cranial epidural disease unless adequately treated and clinically stable at least 4 weeks prior to randomization
=> Symptomatic or impending spinal cord compression or cauda equina syndrome
=> Concomitant anticoagulation with oral anticoagulants (some specific exceptions apply)
=> Administration of a live, attenuated vaccine within 30 days prior to randomization
=> Systematic treatment with, or any condition requiring, either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to randomization
=> Uncontrolled, significant intercurrent or recent illness
=> Major surgery within 4 weeks prior to randomization
=> Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per ECG within 21 days before randomization
=> Inability or unwillingness to swallow pills or receive IV administration
=> Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies
=> Any other active malignancy at time of randomization or diagnosis of another malignancy within 2 years prior to randomization that requires active treatment (some exceptions apply such as locally curable cancers that have apparently been cured).



Poland

Exelixis Clinical Site #82 Recruiting
Bydgoszcz, Poland, 85-796

Exelixis Clinical Site #89 Recruiting
Poznań, Poland, 60-569



https://clinicaltrials.gov/ct2/show/results/NCT04446117
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Zast. MGD019 DART® Protein u pacjentów z nieop. lub mCRPC

Nieprzeczytany postautor: zosia bluszcz » 07 wrz 2021, 23:37

W uproszczeniu - zadaniem MDG019 jest wzmocnienia przeciwnowotworowej odpowiedzi układu odpornościowego.



W pierwszej fazie badania MDG019 był podawany, między innymi, pacjentom z mCRPC z 18 pacjentów, którzy mogli być ewaluowani, 4 odpowiedziało na leczenie, w tym 1 pacjent z rakiem prostaty - potwierdzona całkowita remisja.



A Phase 1, First-in-Human, Open-Label, Dose Escalation and Cohort Expansion Study of MGD019, a Bispecific DART® Protein Binding PD-1 and CTLA-4 in Patients With Unresectable or Metastatic Neoplasms

This Phase 1, open-label study will characterize safety, dose-limiting toxicities (DLTs), and maximum tolerated/administered dose (MTD/MAD) of MGD019.
Dose escalation will occur in a 3+3+3 design in patients with advanced solid tumors of any histology.
Once the MTD/MAD is determined, a Cohort Expansion Phase will be enrolled to further characterize safety and initial anti-tumor activity in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade.

Secondary Outcome Measures :
(...)

Radiographic progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) [ Time Frame: up to 2 years post last treatment ]
Time from first dose to first occurrence of radiographic progression, or death

Prostate specific antigen (PSA) response rate in mCRPC [ Time Frame: up to 2 years post last treatment ]
Percent of patients with 50% or more decline in PSA and confirmed 3 weeks later

Best PSA percent change in mCRPC [ Time Frame: up to 2 years post last treatment ]
Best percent change in PSA from baseline

Duration of PSA response [ Time Frame: up to 2 years post last treatment ]
Time from PSA response to time of PSA progression


Inclusion Criteria:

=> Dose escalation: Patients with histologically proven, unresectable, locally advanced or metastatic solid tumors for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to standard therapy.


Cohort Expansion Phase:
(...)
=> Checkpoint inhibitor-naïve and chemotherapy-naïve (i.e., docetaxel-naïve) mCRPC that has progressed during or following no more than 2 prior lines of an androgen receptor antagonist or androgen synthesis inhibitor (e.g., enzalutamide or abiraterone, respectively), if approved and available, with a PSA value of at least 2 ng/mL and meeting at least one of the following:
=> Progression in measurable disease (RECIST v1.1).
=> Appearance of 2 or more new bone lesions according to Prostate Cancer Working Group 2 (PCWG-2).
=> Rising PSA defined as at least two sequential rises in PSA.
(...)
=> Measurable disease as per RECIST 1.1 for the purpose of response assessment must either (a) not reside in a field that has been subjected to prior radiotherapy or (b) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study enrollment.
=> All patients must have an identified formalin-fixed, paraffin embedded (FFPE) tumor specimen (up to 20 slides or a block) for immunohistochemical evaluation of pharmacodynamic markers of interest. Patients may undergo a fresh tumor biopsy during the screening period if a tumor sample is not available. => => Patients in the mCRPC expansion cohort with bone only disease not amenable to fresh biopsy may be eligible in consultation with the Sponsor.
=> Acceptable laboratory parameters and adequate organ reserve.
(...)

Poland

University Clinical Centre, Early Clinical Trials Unit Recruiting
Gdańsk, Poland, 80-214

Europejskie Centrum Zdrowia Otwock Recruiting
Otwock, Poland, 05-400

Med-Polonia Sp. z.o.o. Recruiting
Poznań, Poland, 60-693

LUX MED Onkologia Sp. z.o.o. Recruiting
Warszawa, Poland, 01-748

Narodowy Instytut Onkologii im Recruiting
Warszawa, Poland, 02-781


https://clinicaltrials.gov/ct2/show/NCT03761017





Wyniki drugiego etapu pierwszej fazy (czyli eskalacji dawki) zostaly omówione w artykule z września 2020.


Sep 20, 2020
MacroGenics Announces Presentation of MGD019 Phase 1 Data at the ESMO Virtual Congress 2020

=> MGD019 well-tolerated with early signals of activity in advanced solid tumors not typically responsive to checkpoint inhibition
=> Recommended Phase 2 dose established for MSS CRC, NSCLC expansion cohorts
(...)
MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, today announced clinical data from the dose escalation portion of a Phase 1 clinical trial of MGD019.
The proffered paper session titled, “A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD019, an Investigational Bispecific PD-1 × CTLA-4 DART® Molecule in Patients with Advanced Solid Tumors,” was presented orally at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 on September 20, 2020, by Dr. Manish R. Sharma, Associate Director of Clinical Research at START Midwest in Grand Rapids, Michigan.

MGD019, a bispecific PD-1 × CTLA-4 DART molecule, was designed to enhance CTLA-4 blockade on dual-expressing, tumor-infiltrating lymphocytes compared to a PD-1/CTLA-4 monoclonal antibody (mAb) combination therapy, while maintaining maximal PD-1 blockade on all PD-1-expressing cells.

Forty-three patients were enrolled in the Phase 1 dose escalation study of MGD019 within a dose range of 0.03 – 10.0 mg/kg, administered every three weeks initially, in a population of heavily pre-treated patients representing a broad range of different types (23) of solid tumors.
There were no dose-limiting toxicities (DLTs).
A total of 28 patients were treated at doses ≥ 3.0 mg/kg administered every three weeks initially.
MGD019 was well-tolerated in patients who received less than 10 mg/kg; the most common treatment-related adverse events over this dosing range were pruritus (23.3%), arthralgia (18.6%), fatigue (18.6%), rash (18.6%), nausea (16.3%) and infusion-related reaction (16.3%). Several Grade 3 adverse events were observed at the 10.0 mg/kg level; however, none were considered dose limiting.
(...)
Of the 18 evaluable patients who received doses ≥ 3.0 mg/kg as of the July 21, 2020 cut-off date, four objective responses have been reported in this trial, including a confirmed complete response in metastatic castration-resistant prostate cancer (mCRPC), confirmed partial responses in microsatellite stable colorectal cancer (MSS CRC) and metastatic type AB thymoma, and an unconfirmed partial response in serous fallopian tube carcinoma.
(...)

http://ir.macrogenics.com/news-releases ... -data-esmo
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