This research study is studying a drug called Paxalisib (GDC-0084) as a possible treatment
for primary central nervous system lymphoma (PCNSL)
This is an open-label, phase 2 study to determine the efficacy of Paxalisib (GDC-0084) in 25
patients with recurrent or refractory primary central nervous system lymphoma (R/R PCNSL.
- The name of the study drug involved in this study is Paxalisib (GDC-0084).
- The research study procedures include: screening for eligibility and study treatment
including evaluations and follow up visits.
- It is expected that about 25 participants will take part in this research study for up
to 24 months as long as there is no serious side effects and disease progression.
This research study is a Phase 2 clinical trial. Phase 2 clinical trials test the safety and
effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied. The U.S. Food and
Drug Administration (FDA) has not approved Paxalisib for this specific disease but it has
been approved for other uses.
Inclusion Criteria:
- Participants must be able to understand and willing to sign a written informed consent
document.
- Participant must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol-related procedures that are not part of normal
subject care.
- Participant must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests, and other requirements of the study.
- Participants must be at least 18 years old on day of signing informed consent.
- Participants must have a Karnofsky Performance Status (KPS) ≥ 70 (see Appendix A).
- Participants must have histologically confirmed R/R primary DLBCL CNS lymphoma (from
brain biopsy, CSF or vitreous biopsy).
- Participants should have evidence of refractory or recurrent disease on MRI with
measurable or evaluable enhancing disease.
- Confirmation of availability of sufficient tissue from brain biopsy for correlative
studies is required prior to enrollment; these samples must be sent to the DFCI
Coordinating Center within 60 days of registration. The following amount of archived
tissue is required: At least 10 but up to 20 unstained formalin-fixed,
paraffin-embedded (FFPE) slides. Histologically confirmed tissue will be required from
the time of relapse or at the time of initial surgery.
- Participants must have recovered to ≤ grade 1 or pre-treatment baseline from
clinically significant toxic effects of prior therapy; exception, participants with ≤
grade 2 neuropathy may be eligible.
- Participant with dexamethasone requirement of ≤ 8mg/day or bioequivalent with
corticosteroid usage at a stable or decreasing dose 2 weeks prior to screening.
- Participants must be able to undergo MRI.
- Participants must demonstrate adequate as defined below (all screening labs should be
performed within 14 days of treatment initiation):
- Hematology
- White Blood Count (WBC) ≥ 2 K/µL
- Platelet count ≥ 100 K/µL
- Absolute Neutrophil Count ≥ 1.5 K/µL
- Hemoglobin > 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without
erythropoietin dependency and without packed red blood cell (pRBC)
transfusion within last 2 weeks)
- Biochemistry
- Serum creatinine ≤1.5 x institutional ULN OR Measured or calculated
creatinine clearance ≥30 mL/min for participant with creatinine levels >1.5
× institutional ULN (Creatinine clearance should be calculated per
institutional standard)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x
ULN (≤5 × ULN for participants with liver metastases)
- Total bilirubin (TBILI) ≤ 1.5 x institutional ULN (except subjects with
Gilbert Syndrome who must have a total bilirubin level of < 3.0 x
institutional ULN) OR Direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN)
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy within 72
hours prior to registration.
- WOCBP who are sexually active must use highly effective methods of contraception
during treatment and for 28 days after the last dose of paxalisib. For male subjects
with a pregnant or non-pregnant WOCBP partner, contraception measures are required
during treatment and for 28 days after the last dose of paxalisib.
The subject, in consultation with the investigator, will select the most appropriate method
of contraception from the permitted list of contraception methods, and site personnel will
instruct the subject in its consistent and correct use as needed.
In addition, the investigator will instruct the subject to notify the site immediately if
pregnancy of the subject or their partner is known or suspected.
Highly effective methods of contraception are those that, alone or in combination, result
in a failure rate of less than 1% per year when used consistently and correctly and
include:
- Established use of oral, injected, or implanted hormonal methods of contraception
- Correctly placed intrauterine device (IUD) or intrauterine system (IUS)
- Male condom or female condom used WITH a spermicide (i.e., foam, gel, film, cream)
- Male sterilization with appropriately confirmed absence of sperm in the post-vasectomy
ejaculate
- Bilateral tubal ligation or bilateral salpingectomy
Exclusion Criteria:
- Participants unable to undergo MRI brain.
- Participants with active systemic disease.
- Participants with uncontrolled intercurrent illness.
- Participants with prior exposure to mTOR/PI3K inhibitors
- Prior malignancy (or any other malignancy requiring active treatment), except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
superficial bladder cancer or other cancer from which the subject has been disease
free for ≥ 3 years.
- Participants who have received prior systemic anti-cancer therapy including
investigational agents or radiotherapy within 4 weeks OR 5 half-lives prior to dosing,
whichever is shorter. Note: Participants must have recovered from all AEs due to
previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may
be eligible.
- Participants who have difficulty with or are unable to swallow oral medication or have
significant gastrointestinal disease that would limit absorption of oral medication.
- Known history of infection with HIV, prior history of PML or any active significant
infection (eg, bacterial, viral, or fungal).
- Known history of hypersensitivity or anaphylaxis to paxalisib including active product
or excipient components.
- Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer which
may have an effect of the metabolism of paxalisib.
- Participants with uncontrolled medical comorbidities per investigator discretion
including but not limited to interstitial lung disease, severe dyspnea at rest or
requiring oxygen therapy, pre-exisiting Crohn's disease or ulcerative colitis or
pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea.
- Participants with uncontrolled type I or II diabetes mellitus. Uncontrolled diabetes
is defined as HbA1c >9% in addition to fasting glucose >140mg/dL on at least 2
occasions within 14 days prior to registration.
- Participants with uncontrolled hypertension despite optimal medical management (per
investigator's assessment).
- Hepatitis B or C serologic status: subjects who are hepatitis B core antibody
(anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need
to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA
PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis
B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will
need to have a negative PCR result to be eligible. Those who are hepatitis C PCR
positive will be excluded.
- Breast feeding or pregnant
- Concurrent participation in another therapeutic trial.
