Inclusion Criteria:
Screening Phase, All Participants.
- - Participant and/or guardian can understand and will sign a written informed consent
document according to institutional guidelines.
- - Before patient screening and registration, written informed consent, also concerning
data and sample transfer, must be given according to ICH/GCP and national/local
regulations.
- - Children, adolescents, and young adults with relapsed/progressive AT/RT, MRT, or
synchronous/metachronous rhabdoid tumor that is histologically confirmed by the
enrolling institution.
Patients must have failed at least one frontline therapy other
than surgery to be eligible.
- - Age at enrollment ≥ 6 months to 25 years.
- - Tumor sample is available from the time of diagnosis or relapse.
If tumor sample is
not available for deposition but molecular analysis was performed using a non-INFORM
registry or non-CLINGEN molecular pipeline, transfer of molecular data (DNA
methylation, whole exome and RNA sequencing) must be completed prior to enrollment.
However, these tests will have to be completed in a CLIA certified facility.
- - Patient has fully recovered from the acute toxic effects of chemotherapy,
immunotherapy, or radiation therapy or is anticipated to do so prior to enrolling on
this study:
- Myelosuppressive chemotherapy: patient has not received myelosuppressive
chemotherapy within 3 weeks of enrollment onto this study (4 and 6 weeks if prior
temozolomide and nitrosourea, respectively).
- - Hematopoietic growth factors: at least 7 days must have elapsed since the
completion of therapy with a growth factor.
At least 14 days must have elapsed
after receiving pegfilgrastim or biosimilar growth factor.
- - Biologic anti-neoplastic agent (except monoclonal antibodies): at least 7 days
must have elapsed since completion of therapy with a biologic agent prior to
enrollment.
For agents that have known adverse events occurring beyond 7 days
after administration, this period prior to enrollment must be extended beyond the
7 days, during which adverse events are known to occur, up to a maximum of 30
days prior to initiation of study treatment.
- - Monoclonal antibodies: Thirty days or at least three half-lives must have elapsed
since prior therapy that included a monoclonal antibody, whichever is later prior
to initiation of study treatment.
- - Treatment with cellular therapy (e.g., CAR-T cell infusion) for anti-neoplastic
intent within 30 days prior to initiation of study treatment.
- - Radiation therapy: at least 3 months must have elapsed since any previous
irradiation to the site of disease prior to study enrollment, unless measurable
disease is confirmed by biopsy or is present at a site separate from the
irradiated area or meets CSF criteria for enrollment.
Inclusion Criteria:
Dose-Finding/Safety Phase and Expansion Phase.
- - Disease that is measurable as defined by RAPNO criteria or RECIST v1.1 (as
appropriate).
A patient who has no measurable disease will be allowed to enroll if one
of the following criteria is met:
- - there is evidence of leptomeningeal disease.
- - CSF presence of tumor cells by cytology confirmed on 2 separate occasions at
least 1 week apart.
- - Adequate performance status:
- Patients <16 years of age: Lansky ≥50%
- Patients ≥16 years of age: Karnofsky ≥50%
- Transient states like infections can be accepted, stable disabilities resulting
from disease/surgery (posterior fossa syndrome, hemiparesis, amputations, etc.)
can be accepted and will not be considered for Lansky/ Karnofsky assessments.
- - Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at
least 1 week before study enrollment.
- - Patient can swallow oral study medication or should have a nasogastric for minimum
size of the NG tube that may be used) or G-tube for the administration of the
medication.
- - Females of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to enrollment.
- - For females of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse or use contraception, agreement to refrain from donating eggs.
- - For males: agreement to remain abstinent (refrain from heterosexual intercourse or use
a condom, and agreement to refrain from donating sperm.
- - Absence of any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule; those
conditions should be discussed with the patient before registration in the trial.
- - No prior therapy with the combination of MDM2 inhibitors and XPO1 inhibitors.
- - Adequate end-organ function defined by the following laboratory results obtained
within 14 days prior to initiation of study drug:
- Bone marrow function: normal bone marrow function as defined by:
- a hemoglobin concentration >8 g/dL (with or without support);
- absolute neutrophil count (ANC) > 1,000/mm3, and.
- - platelet count >75,000/ mm3 (unsupported for 72 hours)
- Adequate renal function as defined by CrCl ≥60 mL/min/1.73 m2.
- - Adequate liver function as defined by alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) concentration ≤ 3 x upper limit of normal (ULN)
per institutional practice and total bilirubin ≤ 1.5 × ULN for age.
Serum albumin
≥ 2 g/dL.
- - Adequate Pancreatic Function defined as:
- Serum amylase ≤ 1.5 x ULN as per institutional practice.
- - Serum lipase ≤ 1.5 x ULN as per institutional practice.
- - Adequate cardiac function as defined by:
- ECG with normal QTc interval < 450 ms as determined by Fridericia correction.
- - Fractional shortening (FS) ≥28% or left ventricular ejection fraction (LVEF) ≥50%
as determined by echocardiography or multigated acquisition scan (MUGA)within 28
days prior to initiation of study therapy.
- - Depending on institutional standard, either FS or LVEF is adequate for
enrollment if only one value is measured; if both values are measured, then
both values must meet the above criteria.
- - Life expectancy ≥ 3 months, in the investigator's judgment.
Exclusion Criteria:
Screening Phase.
- - Significant nausea and vomiting (CTCAEv5 grade 3 or more), chronic diarrhea,
malabsorption despite maximal supportive care or significant small bowel resection
that, in the opinion of the investigator, would preclude adequate absorption.
- - Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
Known active
hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g.,
hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B
virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis
B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be
performed in these patients prior to study treatment. Patients with a known history of
hepatitis C virus infection and positive for hepatitis C virus (HCV) antibody are
eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- - Clinically significant, uncontrolled heart disease.
- - Pregnant or lactating women at the time of enrollment.
Exclusion Criteria Dose Finding/Safety Phase and Expansion Phase, All Cohorts.
- - Major surgery within 21 days of the first dose or anticipate need for major surgical
procedure during the cycle of the study.
Gastrostomy tube placement,
ventriculo-peritoneal shunt, ommaya reservoir placement, endoscopic ventriculostomy,
tumor biopsy and insertion of central venous access devices are not considered major
surgery.
- - Myeloablative therapy with autologous hematopoietic stem cell rescue within 30 days or
allogeneic hematopoietic stem cell rescue within 100 days of study treatment
initiation.
- - Received the following within 7 days prior to initiation of study treatment.
- - Strong CYP2C8 inhibitors.
- - Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the
initiation of study treatment.
- - Patients unable to temporarily interrupt treatment with oral or parenteral
anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment with
aspirin [> 325 mg/day], clopidogrel, dabigatran, apixaban, rivaroxaban) during the
treatment phase.
These agents must be discontinued 7 days (or 5 half-lives), whichever
is longer prior to the start of study medication.
- - Infection considered by the investigator to be clinically uncontrolled or of
unacceptable risk to the patient upon induction of neutropenia, including patients who
are, or should be on antimicrobial agents for the treatment of active infection such
as the following:
- Fungal infection other than mucosal candidiasis, within <2 weeks of completing
appropriate systemic antifungal therapy.
- - Bacterial infection with positive cultures in the 7 days prior to dosing.
- - Patients who have received <5 days of appropriate antibiotic or antiviral therapy
for an identified infection.
- - Neutropenic fever considered infection-related within 72 hours prior to dosing.
- - History of symptomatic Clostridium difficile (C.
diff infection that has since
resolved and patient has normal stool consistency and frequency and/or a negative
C diff stool test.
- - Biopsy confirmed radiation therapy induced pseudoprogression in CNS tumors.
- - History of hypersensitivity to the investigational medicinal product or to any drug
with similar chemical structure or to any excipient present in the pharmaceutical form
of the investigational medicinal product.
- - Should not be receiving any other anti-cancer treatment.
- - Pregnant or breastfeeding females, or intending to become pregnant during the study.
- - Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
28 weeks after stopping study therapy are not eligible.
- Presence of any CTCAE ≥ Grade 2 acute clinically significant treatment-related
toxicity with the exception of alopecia, ototoxicity, peripheral neuropathy and
parameters otherwise permitted in the inclusion criteria (e.g. hematological criteria)
