INCB7839 dosing will begin at 120 mg/m2/dose BID which is equivalent to the adult RP2D (200 mg PO BID) based on a typical adult size of 1.67m2. The INCB7839 dose may be decreased to 80 mg/m2/dose BID if the staring dose is not tolerable. 28 consecutive days (4 weeks) will constitute one course. Patients may continue to receive INCB7839 for 26 courses (approximately 2 years).

Glioblastoma Multiforme

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

DIPG

High-grade Astrocytoma NOS

CNS Primary Tumor, NOS (Malignant Glioma)

INCB7839

Children's Hospital Los Angeles

Lucile Packard Children Hospital Stanford University

Children's Hospital Colorado

Children's National Medical Center

Children's Healthcare of Atlanta

Lurie Childrens Hospital-Chicago

National Cancer Institute Pediatric Oncology Branch

Dana Farber Cancer Institute

Memorial Sloan Kettering Cancer Center

Cincinnati Children Hospital Medical Center

Children Hospital of Pittsburgh of UPMC

St. Jude Children Research Hospital

Baylor College of Medicine

INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas

A Phase I Study of the Adam-10 Inhibitor, INCB7839 in Children With Recurrent/Progressive High-Grade Gliomas to Target Microenvironmental Neuroligin-3

Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0.

To estimate the maximum tolerated dose (MTD) and/or recommend Phase II dose (RP2D) of INCB7839 administered orally in children with recurrent/progressive high-grade glioma.

The area under the curve (AUC) will be calculated based on the course 1 days 1 and 2 pharmacokinetic samples.

The maximum concentration [CMAX] will be calculated based on the course 1 days 1 and 2 pharmacokinetic samples.

The apparent oral clearance [CL/F] will be calculated based on the course 1 days 1 and 2 pharmacokinetic samples.

The time to reach CMAX [TMAX] will be calculated based on the course 1 days 1 and 2 pharmacokinetic samples.

The progression-free survival will be reported.

The duration of response will be reported.

HER2 extracellular domain in serum will be reported.

Neuroligin-3 (NLGN3) in cerebral spinal fluid will be reported.

The maximum concentration [CMAX] will be calculated based on the CSF pharmacokinetic samples.

Pediatric Brain Tumor Consortium

This is a phase I study and we will use a design similar to the Rolling-6 design and open 6 slots initially on Dose level 1. If we observe no-more than 1 DLT in these 6 subjects then we would expand this cohort to at least 12 patients for PK and additional safety information. If more than 1 DLT is observed on dose level 1 in 2-6 subjects, then further enrollment to dose level 1 will stop, the dose will be de-escalated to dose level 0 and the same approach will be repeated. Based on the above-outlined de-escalation rules, if dose level 0 is found to be too toxic, then the trial will be closed to accrual and the merits of amending or closing the trial permanently will be reconsidered.

EOPE: PE starting before 34 weeks gestation Severe PE (Blood pressure more than 160/ 110 mm Hg on 2 occasions 2 hours to 2 weeks apart and proteinuria ( 24-hour urine protein >2000 mg/d).

Healthy Pregnant women who come for termination of pregnancy by vaginal delivery or CS between 28-34 weeks gestational age.

Preeclampsia

A villus tissue (2.5 cm * 2.5 cm * 2.5 cm) will be cut off immediately from the center of placenta, avoiding the area of infarction, bleeding or calcification. After being washed with normal saline, the tissue will be preserved in liquid nitro¬gen at once for subsequent detection of miR-452 and MMP-9 expression by real time PCR (r-PCR). During this procedure total RNA will be extracted including miR-452 and mRNA of MMP-9. Then by reverse transcriptase RNA will be converted into DNA which will be amplification during the PCR, i.e. in real-time, and not at its end, as in conventional PCR. Expression of miR-452 and MMP-9 will be estimated and correlated with each other.

real time PCR (rPCR)

Faculty of Medicine

miRNA-452 in Patients With Preeclampsia and Its Correlation With MMP-9

Expression of miRNA-452 in Patients With Early Onset Preeclampsia and Its Correlation With MMP-9

weight the placenta and fetus in kilograms

FYAli

principal investigator

Assiut University

Nelfinavir in combination with Cisplatin and Pelvic Radiation Therapy

Cervical Cancer

Nelfinavir (NFV) will be prescribed orally twice daily for 7 days prior to initiation of cisplatin and pelvic radiation at the starting dose level, 875 mg BID

Nelfinavir

Cisplatin at 40 mg/m2 (maximum total dose of 70 mg per week), will be infused intravenously once per week on either Day 1, 2, 3, 4, or 5 of weeks 2 to 6, preferably approximately four hours prior to radiation therapy. One additional cycle of cisplatin will be given either week 7 or 8 for a total of 6 cycles of cisplatin. Patients are not to be dosed more than 70 mg/week.

Cisplatin

Pelvic external beam radiation therapy (PEBRT) will be delivered in combination with weekly IV cisplatin (40mg/mg2) and twice daily oral NFV.PEBRT should be delivered once each day during the business week (Monday to Friday) according to the acceptable standards of care as prescribed by the treating radiation oncologist(s). The radiation therapy should consist of whole pelvic external beam radiation therapy (WPEBRT) with or without a parametrial boost (PB). PEBRT will be interdigitated with one administration of intrauterine brachytherapy (BT) given on any business day of week 7 or 8.

Pelvic External Beam Radiation Therapy

PEBRT will be interdigitated with one administration of intrauterine brachytherapy (BT) given on any business day of week 7 or 8.

Brachytherapy

Serum levels of Nelfinavir will be assayed at the following 3 time points: 5-8 days after initiation of NFV single agent (on Day 5, 6, or 7 of week 1 or day 1 of week 2), 1 week after combined NFV and cisplatin pelvic radiation (on day 15, 16, or 17 if start on Monday) for measurement of steady state, and at the completion of treatment (within the last 3 days of radiation in week 6). Blood samples will be taken before drug administration on the day of the sample to make sure the concentrations are actually at a minimum and before tumor biopsies.

Pharmacokinetic Sampling

Three punch biopsies of cervical tumor will be obtained during office visit at each time point (for PCR, IHC, and banked for future research). NFV serum levels will be obtained once NFV has been started (day 5-8 pre chemoradiation and at completion of chemoradiation) before each cervical biopsy

Cervical Biopsy

Pre-Treatment, at the end of treatment +/- 1 week, every 3 months +/- 2 weeks after therapy (x 1 year)

Pelvic Examination

Recommended. Every 3 months +/- 2 weeks after therapy (x 1 year)

Pap Smear

Required in patients with history of hearing loss; 28 days within starting treatment and every other cycle.

Audiogram

Proctoscopy

Cytoscopy

Renal Ultrasound

CT Scan of Chest/Abdomen/Pelvis, pre-treatment,Immediately at end of trial +/- 1 week, Every 3 months +/- 2 weeks after therapy (x 1 year)

CT Scan

In lieu of CT Scan, pre-treatment,Immediately at end of trial +/- 1 week, Every 3 months +/- 2 weeks after therapy (x 1 year)

Whole Body PET/CT Scan

University of Miami

Safety Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy to Treat Cervical Cancer

Phase 1 Study of Nelfinavir Added to Cisplatin Chemotherapy Concurrent With Pelvic Radiation for Locally Advanced Cervical Cancer (II-IVA)

Number of Patients with Adverse Events in Phase 1 Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy

Maximum tolerable Phase II dose of Nelfinavir in combination with Cisplatin and Pelvic Radiation Therapy.

To determine the levels of Akt activity (and downstream effectors such as pGSK3, pEBP1) and p16INK4A in addition to the presence of Human Papilloma Virus (HPV) 16 and18,and E6/E7 RNA in cervical biopsy specimens of patients at three different time points (1. pre-nelfinavir, pre-radiation, 2. while on nelfinavir, pre-radiation, 3. at completion of radiation therapy), and correlate the levels of these markers to serum Nelfinavir levels from blood drawn at the day of the biopsy.

Tumor response to protocol therapy will be measured using Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

Progression-Free Survival is the period from start of treatment until documented disease progression or death from any cause. For surviving patients without progression, progression-free survival will be censored at the last date of documented progression-free status.

Survival is the observed length of life from start of treatment to death. For surviving patients, follow-up will be censored at the date of last contact.

glioma/protease

INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas

miRNA-452 in Patients With Preeclampsia and Its Correlation With MMP-9

Safety Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy to Treat Cervical Cancer

A Trial of the Protease Inhibitor Nelfinavir and Concurrent Radiation and Temozolomide in Patients With WHO Grade IV Glioma

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