Study in Children and Adolescents of 177Lu-DOTATATE (Lutathera®) Combined with the PARP Inhibitor Olaparib for the Treatment of Recurrent or Relapsed Solid Tumours Expressing Somatostatin Receptor (SSTR) (LuPARPed).
Relapsed/refractory (R/R) solid tumours at the paediatric age have a dismal prognosis [5-year overall survival (OS) <20%. There is growing evidence about the somatostatin receptor (SSTR) expression in paediatric tumours, which opens a new diagnostic and therapeutic tool. Somatostatin receptor-targeted therapy with 177Lu-DOTA0-Tyr3-octreotate (177[Lu]Lu DOTA-TATE, 177Lu-DOTATATE, Lutathera®) has been approved by the EMA (2017) and the FDA (2018) for the treatment of adults with midgut neuroendocrine tumours after the excellent results achieved in the phase III NETTER-1 study. 177Lu-DOTATATE is already being explored as monotherapy in children with R/R high-risk neuroblastoma, CNS tumours or meningiomas in 2 pilot studies and 4 clinical trials (ISRCTN98918118, NCT04903899, NCT03966651, NCT05278208). There are two on going clinical trials exploring the recommended phase 2 dose (RP2D) of 177Lu-DOTATATE in children <12 years old, but results are still pending. The results show promising but insufficient results. Because of its beta particle emission, 177Lu-DOTATATE mainly produces DNA single-strand breaks (SSBs) that are easily repaired by the organism. In order to enhance its effect, the investigators propose its combination with PARP inhibitors (iPARP) so that the SSBs could not be repaired and would lead to the formation of DNA double strand breaks (DSBs) and, subsequently, to cell death. This combination is already being explored in different clinical trials in adults with neuroendocrine tumours and prostate cancer. An interesting study analysed the perfect scheme for the 177Lu-DOTATATE and olaparib combination and concluded that olaparib should be delayed 24 hours after 177Lu-DOTATATE administration in order to facilitate normal tissue repair without decreasing antitumoural activity. It also concludes that there is no benefit in continuing olaparib after 4 weeks of continuous treatment. Olaparib has also been administered in children and there is today a recommended phase 2 dose (187.5 mg/m2 BID)
Phase
2Span
274 weeksSponsor
Fundación de investigación HMBoadilla del Monte, Madrid
Recruiting
Computerized Registry of Patients With Venous Thromboembolism (RIETE)
The RIETE Registry pretends the improvement of care of patients with thromboembolic disease. Very often the investigators pose serious doubts on how to manage a specific patient. Sometimes because it is a patient with thrombocytopenia, a pregnant woman, a patient with a recent cerebral bleeding or cerebral metastasis, a patient with gastroduodenal ulcer or hepatic cirrhosis. There is no clinical evidence about how the investigators should manage these patients and the investigators have to individualize its management. The bibliography available is not of much help. Only if the investigators have a database with a sufficient number of cases, they may be able to make evidence based decisions. This database on the Internet will allow the investigators to consult and obtain an immediate response when taking care of a patient who needs an individualized management. After introducing the patient the investigators will automatically obtain the data of all patients with similar clinical profiles. And this will help the investigators to identify high-risk patients and thus facilitate them preventing possible future complications.
Phase
N/ASpan
1401 weeksSponsor
Manuel MonrealBoadilla del Monte, Madrid
Recruiting
Study of 2 Medicines (Aztreonam and Avibactam) Compared to Best Available Therapy for Serious Gram-negative Infections
- Following informed consent, potential participants who are hospitalized, receiving IV antibiotics for less than 24 hours within 48 hours of randomization or failed antibiotic therapy for greater than 48 hours and have suspected/known gram-negative bacterial infections with a complex intra-abdominal infection (cIAI), complex urinary tract (cUTI), blood stream infection (BSI), hospital acquired pneumonia or ventilator associated pneumonia (HAP/VAP) will be screened. - Although cultures are required, isolation of the causative pathogen is not a criteria for enrollment. - cUTI participants requiring systemic prophylactic antibiotics for any reason at screening are allowed to enter the study provided they discontinue this medication prior to first study drug dose. - If the participant satisfies the inclusion and exclusion requirements, the participant will be randomly enrolled in a ratio of 3 iv ATM-AVI for each iv BAT. - A total of 48 participants at approximately 33 sites will be randomized using interactive response technology (IRT). - The study will be multicenter, international and open label with a single blinded observer assigned by each investigational site. - There will be 4 cohorts with ages 12 to less than 18 years (Cohort 1), 6 to less than 12 years (Cohort 2), 2 to less than 6 years (Cohort 3) and 9 months to less than 2 years (Cohort 4). - Each cohort will have 12 participants for a total of 48 participants. - Cohorts 1 and 2 will be enrolled simultaneously. - - Cohort 3 will begin enrollment after the first 4 participants complete Cohort 2 and PK data and safety have been reviewed by the sponsor and an external data monitoring committee (DMC). Then ATM-AVI dose may be adjusted as needed. - Cohort 4 will begin enrollment after the first 4 participants completed Cohort 3 and the PK data have been reviewed by the sponsor and the DMC. Then the ATM-AVI dose may be adjusted as needed. - After 4 participants complete Cohort 4 the PK data will be review by the sponsor and DMC and then the ATM-AVI dose may be adjusted as needed. - Enrollment will not be paused during the PK data reviews of the first 4 ATM-AVI participants in a cohort. If the ATM-AVI dose requires adjustment, the cohort 4 number will be increased to 20 with 15 receiving ATM-AVI and 5 BAT. - All participants in the ATM-AVI group will receive an initial ATM-AVI loading dose and then maintenance doses every 6 or 8 hours depending on the participant's weight and kidney function. - ATM-AVI will be infused over 3 hours. - Those with cIAI will receive metronidazole (MTZ). Patients with cIAI and Cockayne Syndrome are excluded due to a risk of severe hepatotoxicity with the use of MTZ. - At the investigator's discretion MTZ will be administered to those with BSI, cUTI or HAP/VAP and an associated anaerobic infection. - MTZ will be administered iv over 20 to 30 minutes starting. - Optional gram-positive coverage with vancomycin, teicoplanin and linezolid is permitted. Daptomycin is only permitted for cIAI and BSI participants. - Coverage with iv aminoglycoside is permitted for Pseudomonas aeruginosa. - Concerning concomitant medications, participants with cUTI may not take prophylactic therapy during study drug treatment. - Systemic antibiotics are not permitted unless the study drug failed, or it is for a remote site infection essential for participant's safety. - Systemic iv antivirals are permitted. - Systemic antifungals should be avoided unless indicated. - Meropenem/carbapenem-type antibiotics cannot be given concomitantly with ATM-AVI. - Probenecid and inhaled antibiotics are to be avoided from informed consent until the end of iv treatment (EOIV). - Antibiotic peritoneal lavage is not permitted. Non-antibiotic lavage is permitted. - The primary endpoints are pharmacokinetics (PK) and safety. - Five PK micro-blood samples of at least 0.1 mL will be drawn. The initial 2 PK micro blood samples will be drawn at 2 hours and 5 hours after the first infusion. The next 3 PK micro-blood samples will be drawn at 15 minutes before, 5 hours and 5 3/4 hours after the 5th infusion or a later infusion. - ATM and AVI clearance (CL), maximum (Cmax) and minimum (Cmin) venous blood concentration, area under the curve (AUC) and half-life (t1/2) will be analyzed. - A blinded observer (BO), assigned by each investigational site, will clinically assess the participants every day. - The BO will evaluate causality of all adverse events (AEs) and serious adverse events (SAEs) while the participant is in the hospital, within 24 hours of the end of iv study drug (EOIV), and within 48 hours of end of treatment for those switched to oral therapy. - For the secondary endpoint of efficacy, the BO will clinically assess the test of cure (TOC) within 7 to 14 days of the last antibiotic treatment. Potential for liver function abnormalities and acute kidney injury will be specifically monitored in addition to standard of care assessments. - Cure is defined as signs and symptoms improved with no further antimicrobial treatment required except for adjunctive gram-positive therapy or for Pseudomonas aeruginosa. - In addition, for cIAI participants, no unplanned drainage or surgical intervention is necessary since the initial surgical procedure. Only for those switched to oral therapy before 14 days, improvement is afebrile with absence of new signs or symptoms and improvement of 1 or more symptoms or signs with no worsening of signs or symptoms. - Failure is defined as death, requirement of antibiotics for the index infection, or discontinuation due to an AE(s). cIAI participants have additional failure criteria of requiring surgical intervention and/or have an infected post-surgical wound(s). - Participant may choose to permanently discontinue and are free to discontinue treatment without further treatment prejudice. Possible reasons for permanent discontinuation are: - Condition under investigation resolved prior to minimum treatment period - AE or any other condition posing a risk to a participant or jeopardizing safety - Investigator, national coordinators, medical monitor, and/or Sponsor decided it is in the best interest of the participant's safety - Positive pregnancy test during the treatment period - Absence of explanation for liver injury and/or increase in liver function tests or acute kidney toxicity - Discontinuation of intervention does not represent withdrawal from the study and participants should remain in the study until the end of the study (EOS).
Phase
2Span
167 weeksSponsor
PfizerBoadilla del Monte, Madrid
Recruiting