| Eligibility |
Inclusion Criteria:
- DOSE ESCALATION: Patients must have a pathogenic or likely pathogenic germline or
somatic defect as determined by local assessment and classification in at least one of
the following:
- Defect in one or more DNA Damage Response (DDR) genes such as: ATM (including ATM
protein loss by IHC), ATRX, ARID1A, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2,
FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, MSH2, NBN, PALB2, RAD51,
RAD51B, RAD51C, RAD51D, or other related genes at the discretion of the principal
investigator in consultation with the MD Anderson Cancer Center Institute for
Personalized Cancer Therapy Precision Oncology Decision Support (PODS) group OR
- PIK3CA hotspot and PTEN mutations
- DOSE EXPANSION: Patients must have a pathogenic or likely pathogenic germline or
somatic defect as determined by local assessment and classification
- Cohort A: ATM deleterious mutation or loss of ATM expression
- Cohort B: Actionable PIK3CA hotspot and PTEN mutations
- Patients must have histological diagnosis of locally advanced (primary or recurrent)
or metastatic solid tumors (except primary central nervous system [CNS] tumors), that
are not amenable form treatment with curative intent or who have refused or are
intolerant of standard therapy
- Availability of a fresh or recent tumor tissue sample from a diagnostic biopsy/surgery
or a metastatic tumor biopsy; the sample must have been obtained with 12 months prior
to study enrollment. When only bone disease is present, an archival tumor tissue
sample obtained within 5 years prior to study enrollment may be accepted for
non-prostate cancer patients and a fresh bone biopsy may be accepted for prostate
cancer patients only
- Patients must be >=18 years of age
- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) version (v)1.1; or patients may have bone only metastatic disease evaluable
by Prostate Cancer Working Group 3 (PCWG3) for subjects with metastatic
castration-resistant prostate cancer (mCRPC), or according to the tumor evaluation
criteria best suited and accepted for the tumor type being evaluated
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Absolute neutrophil count (ANC) >= 1,500/mcL.
- Platelets >= 150,000 / mcL
- Hemoglobin >= 10 g/dL without dependence on erythropoietin support or blood product
support
- Participants must not have received a transfusion (platelets or red blood cells)
within 28 days of the first dose of study intervention. Participants must not have
received administration of granulocyte colony-stimulating factor, erythropoietin, or
thrombopoietic treatments within 14 days of the first dose of study intervention.
Hemoglobin (Hb) value must be met without erythropoietin dependency
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 x
institutional ULN
- Creatinine clearance can be estimated according to the Cockcroft-Gault formula
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =<
5 x ULN for subjects with liver metastases
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
- Patients must be >= 2 weeks beyond treatment with any chemotherapy or other
investigational therapy to include hormonal, biological, or targeted agents; or at
least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter
at the time of treatment initiation
- Women of childbearing potential MUST have a negative serum or urine HCG test unless
prior tubal ligation (>= 1 year before screening), total hysterectomy or menopause
(defined as 12 consecutive months of amenorrhea). Patients should not become pregnant
or breastfeed while on this study. Sexually active patients must agree to use dual
contraception for the duration of study participation and for 120 days after
- Ability to understand and willingness to sign informed consent form prior to
initiation of the study and any study procedures
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other study procedures
- Any medical condition or diagnosis that would likely impair absorption of an orally
administered drug (e.g. gastrectomy, ileal bypass, chronic diarrhea, gastroparesis)
- Inability to comply with the study and follow-up procedures
Exclusion Criteria:
- Inability or unwillingness to swallow pills
- Active infection requiring intravenous (IV) antibiotics or other uncontrolled
intercurrent illness requiring hospitalization. Minor infections, e.g. periodontal
infection or urinary tract infection (UTI), which may be treated with short term oral
antibiotics are allowed
- History of cerebrovascular accident (CVA), myocardial infarction or unstable angina
within the previous 6 months before starting therapy
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has a known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging (as determined by magnetic
resonance imaging [MRI] or computed tomography [CT]) for at least four weeks prior to
the first dose of trial treatment and any neurologic symptoms have returned to
baseline) and have no evidence of new or enlarging brain metastases. Subjects with
previously treated brain metastases may participate provided they are stable (without
evidence of progression by imaging for at least four weeks prior to the first dose of
trial treatment and any neurologic symptoms have returned to baseline), have no
evidence of new or enlarging brain metastases, and are not using steroids > 10mg or
equivalent of prednisone for at least 7 days prior to trial treatment. This exception
does not include carcinomatous meningitis which is excluded regardless of clinical
stability
- Patients with uncontrolled Type I or II diabetes mellitus (DM); uncontrolled DM is
defined as hemoglobin A1c (HbA1c) > 8.5% and a fasting blood glucose of > 120 mg/dL
within 14 days prior to trial entry
- Patients with congestive heart failure > New York Heart Association (NYHA) Class 2,
unstable angina, or uncontrolled hypertension despite optimal management
- Patients with history or concurrent condition of interstitial lung disease or any
severity and/or severely impaired lung function
- Patients with prior anti-cancer therapy within 2 weeks prior to study enrollment or
prior radiation therapy within 2 weeks prior to study enrollment. Prior palliative
radiotherapy to metastatic lesion(s) is permitted, provided it has been completed at
least 2 days prior to study enrollment and no clinically significant toxicities are
expected (e.g. mucositis, esophagitis)
- Patients who have undergone major surgery and have not recovered prior to study
enrollment
- Patients who have a known prior severe hypersensitivity to investigational products or
any component in their formulations
- Patients with persisting toxicity related to prior therapy (National Cancer Institute
[NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0 grade > 1). However,
alopecia and sensory neuropathy grade =< 2, or other grade =< 2 adverse events not
constituting a safety risk, based on the investigator's judgement, are acceptable
- All participants must be screened for hepatitis B virus (HBV) and hepatitis C virus
(HCV) up to 28 days prior to start of study intervention, using the routine hepatitis
virus laboratorial panel.
- Participants positive for hepatitis B surface antigen (HBsAg) or hepatitis B core
antibody (HBcAb) will be eligible if they are negative for HBV deoxyribonucleic
acid (DNA); participants positive for anti-HCV will be eligible if they are
negative for HCV ribonucleic acid (RNA)
- Patients who have received external beam radiation therapy (EBRT) to > 50% of the
total body reserve of active bone marrow mass involvement. This may be difficult to
quantify and will be left to physician discretion
- Positive cytomegalovirus (CMV) polymerase chain reaction (PCR) test at baseline
- Pregnant female patients; breastfeeding female patients; fertile male patients; and
female patients of childbearing potential who are unwilling or unable to use 2 methods
of contraception for the duration of the study and for at least 120 days after the
last dose of study drugs for female patients or 120 days after the last dose of study
drugs for male patients, whichever is later for the individual patient. 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. These
methods include:
- Established use of oral, inserted, or injected or implanted hormonal methods of
contraception are allowed provided the patient remains on the same treatment
throughout the entire study and has been using that hormonal contraceptive for an
adequate period of time to ensure effectiveness
- Correctly placed copper containing intrauterine device (IUD)
- Male condom or female condom used with spermicide (i.e. foam, gel, film, cream or
suppository)
- Male sterilization with appropriately confirmed absence of sperm in the
post-vasectomy ejaculate
- Bilateral tubal ligation or bilateral oophorectomy
|
