A Personalized Medicine Study for Patients With Advanced Cancer of the Breast, Prostate, Pancreas or Those With Refractory Acute Myelogenous Leukemia

PRIMARY OBJECTIVES:

I. To determine the feasibility of implementing an individualized treatment strategy across
several different cancer types based upon a comprehensive assessment of tumor and patient
characteristics.

SECONDARY OBJECTIVES:

I. To describe the tolerability of implementing an individualized treatment strategy,
particularly by measuring unanticipated toxicity associated with the administration of
different combinations of two therapeutic agents given to an individual participant.

II. To determine the response rate, within each of the four disease cohorts (i.e., BCa, PCa,
PanCa, AML).

III. To determine the progression-free survival, within each of the four disease cohorts
(i.e., BCa, PCa, PanCa, AML).

IV. To determine overall and disease-specific survival within each of the four disease
cohorts (i.e., BCa, PCa, PanCa, AML).

V. To determine the time to decline in a participant's ability to perform activities of daily
living.

EXPLORATORY OBJECTIVES:

I. To measure quality of life among enrolled participants. II. To evaluate immune response
for participants receiving immunomodulatory therapy.

III. To correlate baseline and on study clinical parameters with tumor characteristics as
assessed by clinical and research-based analytics.

IV. To enhance integration of clinical and basic research activities, so as to advance our
understanding of cancer biology and how that knowledge can be used to improve patient care.

V. To assess tumor characteristics and, ultimately, our understanding of human cancer biology
using of a panel of research-based analytical assays.

OUTLINE: This is an open-label, Phase Ib that consists of novel combination drug treatment
regimens derived from a set list of 35 drug agents or chemotherapeutic combinations.

Participants will undergo an initial tumor tissue/cell biopsy (Biopsy #1) which will be
performed prior to initiation of their last standard of care therapy. This biopsy will be
analyzed using Clinical Study Analytics and imaging assessments to derive an in-depth
cellular and molecular profile of an individual participant's cancer. The findings will be
presented to a dedicated clinical tumor board that will be convened to exercise its
collective clinical judgment, following a defined SMMART drug decision logic to assign an
individualized SMMART therapeutic regimen (Therapy #1). This therapeutic regimen consists of
a rational combination of two drugs. These drug agents may be administered in combination,
either concurrently or serially depending on their respective pharmacology.

Participants that have progressive disease following completion of their standard of care
therapy may begin their selected SMMART therapeutic regimen (Therapy #1). Participants will
undergo a second biopsy (Biopsy #2) prior to starting Therapy #1. The biopsy and imaging
assessments will be analyzed (similar to Biopsy #1) and findings will be presented a second
clinical tumor board that will determine a second on-study therapeutic regimen (Therapy #2).

Therapy #1 and all subsequent therapies will involve two drugs (Drug A and Drug B), whose
doses will be escalated within individual patients over time. As described in detail below,
escalation will occur on a monthly basis and is anticipated to occur as follows: first month
-- 100% dose Drug A+25% dose Drug B; second month --100% dose Drug A + 50% dose Drug B; third
month -- 100% dose Drug A + 100% dose Drug B.

After three months of Therapy #1, participants will undergo Biopsy #3. The tumor biopsy along
with imaging assessments will be will be used to inform a third clinical tumor board.
Following the same schema described for choosing Therapies #1 and #2, this tumor board will
deliberate on the results of to assign a third Therapy #3.

After 3 cycles (with a cycle equated to 28 days) of Therapy #1, participants demonstrating
stable disease (SD), partial response (Pr), or complete response (CR) will continue Therapy
#1 for an additional 3 cycles (i.e., an additional 3 months, for a total of 6 cycles or 6
months). If participants clinically progress or cannot tolerate their assigned treatment,
they may be eligible to receive the next assigned therapy (i.e., Therapy #2). This is an
iterative process and continues with each SMMART therapeutic regimen; thus, if participants
show PD while receiving Therapy #2, they may be eligible to receive the next ascribed
treatment regimen (e.g., Therapy #3), and so on. Each therapy will be based on the preceding
biopsy. In general, there is no limit to the number of serial therapeutic regimens a
participant can receive and it is possible for participants to experience PD and remain
on-study. However, participants must continue to meet treatment eligibility criteria.
Recognizing that participants who fail to respond to serial therapeutic regimens will
experience a generalized clinical decline, individuals who experience a decline in their
performance status will not receive any further therapy.

Participants who discontinue therapy or withdraw may participate in follow up which consists
of reimaging and history and physical at least every three months.

Inclusion Criteria:

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

- Participants ≥ 21 years old at time of informed consent. Both men and women and
members of all races and ethnic groups will be included.

- Participants, both men and women, must agree to use an adequate method of
contraception prior to Study entry, for the duration of Study participation, and for 4
months after completion of Study.

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 14 days prior to start of Study drug administration.

- Participants must have histologically documented BCa, PCa, or PanCa, or pathologically
documented AML.

- Participants with BCa, PCa, or AML must have progressed following standard therapy, as
described in detail below for each of these diseases. Patients with PanCa will be
eligible irrespective of prior treatment, inclusive of those who have not received any
prior treatment. Participants who due to medical issues cannot receive other standard
therapy that has been shown to prolong survival will be eligible, if other eligibility
criteria are met.

- Participants in BCa, PCa, or PanCa cohorts must have metastatic disease.

1. For BCa and PanCa and for PCa participants with soft tissue disease, this is
defined by at least one lesion that can be accurately measured in at least one
dimension (longest diameter to be recorded for non-nodal lesions and short axis
for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with
spiral CT scan, per RECIST (v1.1).

2. For PCa, participants with lesions on a bone scan that are considered distinctly
metastatic will also be included.

- Participants in AML cohort must have pathologically confirmed AML per WHO diagnostic
criteria and have their bone marrow biopsy and aspirate reviewed at OHSU.

- Participants in BCa, PanCa, and PCa cohorts, must have lesions meeting the above
criteria also and must be amenable to image guided or direct vision biopsy.

- Participants must not currently be receiving any other investigational agents.

- Participants must have ECOG performance status ≤ 1 (Karnofsky ≥ 80%) and a physician
assessed life expectancy of ≥ 6 months.

- Participants must have adequate organ function (defined in protocol) at time of
registration and within 4 weeks prior to initiating on-protocol treatment.

- Any prior therapy, radiotherapy (except palliative radiation therapy of 30 Gy or
less), or major surgery must have been completed ≥ 4 weeks prior to start of
treatment. All adverse events due to prior therapy have resolved to a Grade 1 or
better (except alopecia and lymphopenia and hematologic toxicity in AML) by start of
treatment. Palliative radiation therapy must have been completed at least 2 weeks
prior to start of treatment. The radiotherapy must not be to a lesion that is included
as measurable disease.

- All potential participants must be discussed with and specifically approved by the
Study PI.

CANCER SPECIFIC INCLUSION CRITERIA: Breast Cancer (BCa)

- Participants must have progressive disease.

- Participants considered to have hormone receptor positive disease and/or those
considered to have HER2 positive disease must have failed all prior therapies
considered to be standard of care based upon hormone receptor and HER2 expression
status.

- Participants who are considered to have failed hormone or HER2 directed therapy but
are still maintained on those respective lines of agents per standard of care practice
will be considered on a case-by-case basis for participation in the Study while still
receiving such agents.

- Participants must be about to begin chemotherapy.

- Participants with triple negative breast cancer (TNBC) who are about to begin a course
of chemotherapy are eligible.

CANCER SPECIFIC INCLUSION CRITERIA: Prostate Cancer (PCa)

- Participants must have progressive disease.

- Participants must have failed at least one line of hormone therapy in the setting of
castrate resistant disease (i.e., individuals must have failed initial androgen
deprivation therapy as well as one line of another hormone therapy).

- Participants must have castrate levels of testosterone and are about to begin
chemotherapy.

CANCER SPECIFIC INCLUSION CRITERIA: Pancreatic Cancer (PanCa)

- Participants with newly diagnosed metastatic disease and are beginning first-line
treatment with a course of chemotherapy are eligible.

1. Participants who have failed prior chemotherapy for metastatic disease and are
about to begin another line of chemotherapy will be considered on a case-by-case
basis.

2. Adjuvant or neo-adjuvant chemotherapy given in the context of local disease will
not count towards number of regimens for metastatic disease.

CANCER SPECIFIC INCLUSION CRITERIA: Acute Myelogenous Leukemia (AML)

- Participants must have primary refractory or relapsed AML with persistent disease
after receiving two intensive regimens (also termed induction regimens).

- Participants who are considered older (i.e., over 60), will be eligible and do not
have to meet the above requirements. Such individuals will evaluated on a case by case
basis, but will have failed an initial induction regimen and are not considered bone
marrow transplant candidates.

- Participants may be on hydroxyurea for purposes of controlling WBC counts at the time
of Study entry (i.e., time of Biopsy #1) and may remain on it during the screening
part of the study.

1. Participants may remain on hydroxyurea through the first two cycles of SMMART
therapy. It is standard practice to take this approach with refractory AML
participants entering onto trials of experimental agents. Continuation of
hydroxyurea beyond first two cycles may be allowed on a case by case basis.
Hydroxyurea will not count as a SMMART Study drug, i.e., they can remain on
hydroxyurea while receiving SMMART Drug A plus Drug B. Co-administration of
hydroxyurea will be appropriately documented on treatment plans and relevant case
report forms.

Exclusion Criteria:

- Participants with metastases to the central nervous system that are considered
uncontrolled and/or were diagnosed within the past 4 weeks of screening for this
Study.

- Participants with certain subtypes of cancer will be excluded. The following list
provides examples but is not all inclusive, and individual situations will be handled
on a case-by-case basis: neuroendocrine PanCa, small cell PCa, unusual subtypes of
BCa, acute promyelocytic leukemia (APL).

- Participants cannot have an active malignancy of another cancer. Those with a history
of prior malignancy will be considered on a case-by-case basis. Guiding examples for
those who can be enrolled include: individuals who have been disease free for >5
years; individuals who are considered to have a high likelihood of being cured (e.g.,
prior history of stage 1 rectal cancer and currently otherwise disease free);
adequately treated localized non-melanomatous skin cancer.

- Participants cannot be on other forms of anti-cancer therapy at the same time, except
as described within this protocol. There must be at least washout period that accounts
for 5 half-lives of last therapy.

1. Participants with PCa will continue treatment with androgen deprivation therapy,
either by prior castration or treatment with LHRH antagonists or agonists, as is
standard practice.

2. Participants with BCa who are HER2 positive may continue to receive anti-HER2
therapy per standard practice guidelines, while participants who are hormone
receptor positive may continue to receive hormone therapy per standard practice
guidelines.

3. Participants with AML may continue to receive hydroxyurea for two cycles of
SMMART therapy, as described in this protocol.

- Participants with medical conditions, inclusive of psychiatric, that in the opinion of
the investigators would jeopardize the patient or the Study will be excluded.

- Participants that are pregnant or breast feeding.

CANCER SPECIFIC EXCLUSION CRITERIA: Breast Cancer (BCa)

- Participants who have already received 3 or more treatment courses with cytotoxic
agents for metastatic disease typically constitute individuals with compromised organ
function and performance status and will generally not be considered eligible.

1. Recognizing that this is not always the case, such individuals will be considered
on a case-by-case basis.

2. Adjuvant chemotherapy will not count towards this number of treatment courses.

CANCER SPECIFIC EXCLUSION CRITERIA: Prostate Cancer (PCa)

- Participants who have already received 2 or more courses with cytotoxic agents
typically constitute individuals with compromised organ function and performance
status and will generally not be considered eligible.

1. Recognizing that this is not always the case, such individuals will be considered
on a case-by-case basis.

2. Chemotherapy administered up front in newly diagnosed metastatic disease (i.e.,
at the time of initiation of androgen deprivation therapy, considered standard of
care) will not count towards this number.

CANCER SPECIFIC EXCLUSION CRITERIA: Acute Myelogenous Leukemia (AML)

- Participants must not be planning to undergo bone marrow transplant.