Phase 1 Study of Niraparib in Combination With Osimertinib in EGFR-Mutated Advanced Lung Cancer

This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved niraparib for this specific
disease but it has been approved for other uses.

The FDA has approved osimertinib as a treatment option for this disease.

Niraparib is a type of drug called a "PARP inhibitor", which blocks DNA (the genetic material
of cells) damage from being repaired or may prevent damage from occurring in the first place.
In cancer treatment, inhibiting PARP may help kill cancer cells through deadly DNA damage.
PARP inhibition may be a treatment option for participants with this type of cancer due to
altered repair and protection of tumor DNA.

Osimertinib is an inhibitor of the epidermal growth factor receptor (EGFR). In this type of
cancer there is a mutation in the EGFR which is allowing the cancer to grow when it is not
supposed to. Osimertinib blocks mutated EGFR, which may cause tumor regression (when the
tumor starts to shrink) and prevent the spread of the cancer.

In this research study, the investigators are looking to see whether the combination of
niraparib and osimertinib is safe and well tolerated and what the best dose of niraparib is
in participants with EGFR-Mutated Advanced Lung Cancer. The investigators also hope that the
combination of niraparib and osimertinib will stop the cancer from growing and spreading.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed stage IV (AJCC 8th
ed.) NSCLC with an activating EGFR mutation as identified in a CLIA-approved
laboratory.

- Presence of evaluable disease, either measure or non-measurable, in accordance with
RECIST 1.1 criteria.

- Participants must have had clinical progression on osimertinib at any prior time,
i.e., intervening therapy between osimertinib and study enrollment is allowed.

- Participants must have access to commercial osimertinib.

- Participants must not have received any prior PARP inhibitor therapy.

- Age minimum 18 years.

- ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A).

- Life expectancy of greater than 6 months.

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥ 9 g/dL

- bilirubin total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤2.0 in patients
with known Gilberts syndrome or liver metastases) OR direct bilirubin ≤ 1 x ULN

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, unless liver
metastases are present, in which case they must be ≤ 5 x ULN

- creatinine ≤ 1.5 x institutional ULN OR

- creatinine clearance ≥50 mL/min using the Cockcroft-Gault equation

- Participants must have undergone a prior tumor biopsy upon clinical progression on
osimertinib. If it was not feasible or medically safe to undergo a biopsy a patient
may enroll with permission of the PI.

- The effects of Niraparib on the developing human fetus are unknown but based on its
mechanism of action Niraparib may cause fetal harm when administered to a pregnant
woman. Women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry through 180 days after the last dose of study treatment. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately. Men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study, for
the duration of study participation, and 4 months after completion of Niraparib
administration.

- Female participant must have a negative urine or serum pregnancy test within 7 days
prior to taking study treatment if of childbearing potential, or is of nonchildbearing
potential. Nonchildbearing potential is defined as follows (by other than medical
reasons):

--≥ 45 years of age and has not had menses for >1 year

- Patients who have been amenorrhoeic for <2 years without history of a
hysterectomy and oophorectomy must have a follicle stimulating hormone value in
the postmenopausal range upon screening evaluation

- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
Documented hysterectomy or oophorectomy must be confirmed with medical records of
the actual procedure or confirmed by an ultrasound. Tubal ligation must be
confirmed with medical records of the actual procedure, otherwise the patient
must be willing to use 2 adequate barrier methods throughout the study, starting
with the screening visit through 180 days after the last dose of study treatment.
See Section 4.4 for a list of acceptable birth control methods. Information must
be captured appropriately within the site's source documents. Note: Abstinence is
acceptable if this is the established and preferred contraception for the
patient.

- Ability to take oral medications whole.

- Participant receiving corticosteroids may continue as long as their dose is stable for
least 4 weeks prior to initiating protocol therapy.

- Participant must agree to not donate blood during the study or for 90 days after the
last dose of study treatment

- Participant must agree not to breastfeed during the study or for 180 days after the
last dose of study treatment.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants must not be simultaneously enrolled in any interventional clinical trial.

- Participants receiving any systemic standard of care or investigational therapy within
4 weeks from the last dose prior to planned study treatment, with the exception of
osimertinib. This time frame may be shortened for participants depending on the
characteristics of the individual therapy, after discussion with the Study PI. For
investigational therapy, the time frame will not be shortened to less than at least 5
half-lives of the investigational agent.

- Patients receiving radiation therapy encompassing > 20% of the bone marrow by
investigator's estimate within 14 days, or any radiation therapy within 7 days from
the last treatment prior to planned study treatment. However, small volume palliative
radiation therapy with no or little bone marrow exposure is allowed at the
investigator's discretion.

- Participants may receive a stable dose of bisphosphonates for bone metastases, before
and during the study as long as these were started at least 4 weeks prior to
treatment.

- Participants who had any major surgery within the past 3 weeks (excluding vascular
access placement, mediastinoscopy, or biopsies performed by an interventional service)
and participant must have recovered from any surgical effects.

- Participants with symptomatic uncontrolled brain or leptomeningeal metastases.
Participants with brain metastases that have been treated with prior radiation therapy
and are stable on a subsequent scan are allowed. Participants with untreated possible
brain metastases that are ≤ 1 cm and asymptomatic are allowed.

- Participants who received a transfusion (platelets, red blood cells) or hematopoetic
growth factors within 4 weeks of study treatment.

- Presence of any of the following cardiac criteria/factors:

- Resting QT interval of >470 msec.

- Any clinically important abnormalities in rhythm, conduction or morphology of resting
ECG, such as complete left bundle branch block, third degree heart block, or second
degree heart block.

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalemia, congenital long QT syndrome, family history of
long QT syndrome, or unexplained sudden death under 40 years of age in first degree
relatives, or any concomitant medication known to prolong the QT interval.

- Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required corticosteroid treatment, or any
evidence of clinically active interstitial lung disease.

- Participants with known hypersensitivity to the components or excipients of niraparib
or osimertinib.

- Participants may not have received prior treatment with anti-PD1, -PDL1, or -CTLA4
inhibitors.

- Participants with a second, clinically active, malignancy. Participants must not have
known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid
leukemia (AML).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, myocardial infarction, major seizure disorder, unstable spinal cord
compression, superior vena cava syndrome, or psychiatric illness/social situations
that would limit compliance with study requirements.

- Participants must not have had any known Grade 3 or 4 anemia, neutropenia or
thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to
the most recent treatment.

- Participants must not have current evidence of any condition, therapy, or laboratory
abnormality (including active or uncontrolled myelosuppression [ie, anemia,
leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the
study or interfere with the patient's participation for the full duration of the study
treatment or that makes it not in the best interest of the patient to participate in
the opinion of the investigator or sponsor.

- Patients must not have known, active hepatitis B/C.

- Known disorder affecting gastrointestinal absorption.

- Patients must not be pregnant or breastfeeding, or expecting to conceive children,
within the projected duration of the study treatment, or for 180 days after the last
dose of study treatment.

- Known HIV-positive participants are ineligible because of the potential for
pharmacokinetic interactions with Niraparib. In addition, these participants may be at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in participants receiving combination
antiretroviral therapy when indicated, However, HIV testing is not required.