A Phase 1-2, Open-Label, Dose-Finding, Proof of Concept, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CX-2009 in Adults with Metastatic or Locally Advanced Unresectable Solid Tumors

Subjects who fulfill the following criteria at Screening will be eligible for
admission into the
study:
1. Histologically confirmed diagnosis of active metastatic or locally advanced
unresectable
solid tumor in subjects who have disease progression after treatment with
available therapies
that are known to confer clinical benefit, or who are intolerant to treatment,
in the following
indications (with guidance for standard treatment below).
For Parts A2, B, C1, C2, D1, and D2, an archival tumor tissue sample must be
submitted to
the central laboratory for evaluation of CD166 expression and demonstrate
confirmed high
CD166 expression by IHC. Biopsy collection for the purpose of determining
eligibility is not
permitted.
Eligible indications, by Part:
* Part A: BC, CRPC, NSCLC (including adenocarcinoma and squamous cell subtypes),
OEC, EC, HNSCC, and CCC;
* Part A2: BC, NSCLC (including adenocarcinoma and squamous cell subtypes), OEC,
EC, and HNSCC;
* Parts B, C2, and D2: TNBC, hormone receptor (HR; ie, estrogen and/or
progesterone)-positive/HER2-negative BC, NSCLC (including adenocarcinoma and
squamous cell subtypes), OEC, and HNSCC; and
* Parts A mTPI-2 cohort, C1, and D1: BC, NSCLC (including adenocarcinoma and
squamous cell subtypes), and HNSCC;
Criterion specific to Parts B, C, and D:
* Subjects must have received the standard prior treatments for metastatic or
advanced
unresectable disease as outlined below, but not more than 3 (<=3) prior lines in
total;
Standard prior treatments, by tumor type:
BC (Parts A, A2, C1, and D1):
* Patients with HER2-positive BC are required to have progressed on
HER2-targeted
therapy (trastuzumab, pertuzumab, and/or T-DM1);
* Estrogen-receptor-positive should have received anti-hormonal therapy, a
CDK4/6
inhibitor, or mTOR inhibitor and progressed; and
* TNBC should have received at least 2 prior lines of therapy;

TNBC (Parts B, C2, and D2):
* Should have received at least 2 prior lines of therapy; and
* Subjects with BReast CAncer gene (BRCA) mutations must be refractory to or
otherwise ineligible for poly adenosine diphosphate-ribose polymerase
inhibitors (eg,
olaparib), if approved and available;
HR-positive/HER2-negative BC (Parts B, C2, and D2):
* Should have received and progressed on an anti-hormonal therapy, targeted
therapy
(CDK4/6 or mTOR inhibitor), or chemotherapy;
* Endocrine refractory should have received at least 3 prior hormonal therapies
and
progressed;
* Post or pre-menopausal subjects receiving ovarian ablation or suppression
must have
progressed on an aromatase inhibitor (AI) in combination with a CDK4/6
inhibitor or
fulvestrant in combination with a CDK4/6 inhibitor; and
* Subjects who progressed within 12 months or while on a non-steroidal AI, must
have
progressed on an mTOR inhibitor and on a combination of exemestane with
everolimus (mTOR);
CRPC (Part A):
* Received at least 1 prior therapy (eg, abiraterone + prednisone, or
docetaxel + prednisone, or enzalutamide);
NSCLC, including adenocarcinoma and squamous cell
subtypes (All Parts):
* Should have received at least 1 platinum-containing regimen. as well as an
anti-PD-1
or anti-PD-L1 therapy; and an ICI should have been
administered if approved and available for the subject*s indication in their
locality
* Subjects harboring genomic aberrations for which FDA-approved targeted
therapy is
available (eg, non-resistant epidermal growth factor receptor [EGFR] mutations,
EGFR T790M mutation, anaplastic lymphoma kinase (ALK) rearrangement, ROS
rearrangement, BRAF V600E mutation) must have received prior treatment with an
FDA-approved targeted therapy. Subjects without actionable mutations or
rearrangements if progression on all available therapy, including platinum-based
combinations, must have received an anti-PD-1/PD-L1 antibody and docetaxel
administered with ramucirumab; and
* Subjects with known EGFR tyrosine kinase (TK)-activating mutations or ALK
rearrangements must have received a tyrosine kinase inhibitor (TKI);
OEC (Parts A, A2, B, C2, D2):
* Non-BRCA mutation (germline or somatic) subjects or subjects with
unknown BRCA mutational status must be platinum-resistant or platinum-refractory
ovarian carcinoma for the expansion cohort;
* Subjects with platinum-resistant disease must have progressed on chemotherapy
plus
bevacizumab; and
* Subjects with BRCA mutations must be refractory to or otherwise ineligible
for poly
adenosine diphosphate ribose polymerase inhibitors (eg, olaparib or rucaparib)
if
approved and available;
EC (Parts A, A2):
* Should have received at least 1 platinum-containing regimen for extra-uterine
or
advanced disease;
HNSCC (All Parts):
* Must have received a platinum-containing regimen and anti-programmed cell
death
protein PD-1 (PD1) if approved and available for subject*s indication in their
locality;
and
* Must have progressed on a taxane, cetuximab, or methotrexate;
CCC (Part A):
* Failed at least 1 prior line of a gemcitabine-containing regimen.
Additional Requirements for Parts D1 and D2:
Must have documented evidence of PD-L1-positive tumor status.

2. Agrees to provide tumor tissue; archival, new, or recent acquisition
confirmed to be available
prior to initiation of study drug for performance of correlative tissue and
cellular studies from
a tumor site not previously irradiated:
* Part A2: subjects must consent to an on-treatment tumor biopsy at 3 to 5 days
after the first dose of CX-2009; and
* Parts B and C2 (monotherapy dose expansions): at least 7 subjects of each
tumor type must consent to provide a
pretreatment and on-treatment tumor biopsy and peripheral blood samples 3 to 5
days after the
first dose of CX-2009.

3. Evaluable or measurable disease required for dose escalation (Part A) and
measurable disease
per RECIST v1.1 required for Parts A2, B, C1, C2, D1, and D2;
4. Subjects with treated brain metastases are eligible if the brain metastases
are stable and the
subject does not require radiation therapy, or steroids. Active screening for
brain metastases
(eg, brain computed tomography or magnetic resonance imaging) is not required;
5. At least 18 years of age;
6. Eastern Cooperative Oncology Group performance status of 0 or 1;
7. Anticipated life expectancy of at least 3 months;
8. Screening laboratory values must meet the following criteria:
* Absolute neutrophil count >=1500/uL;
* Platelet count >=100 x 10 ^3 /uL (must not have been transfused within
previous
10 days);
* Hemoglobin >=9.0 g/dL (may have been transfused);
* Serum creatinine <=1.5 x institution*s upper limit of normal (ULN);
* Aspartate aminotransferase (AST) <=2.5 x institution*s ULN; alanine
aminotransferase
(ALT) <=2.5 x institution*s ULN (AST, ALT <5 x ULN for subjects with CCC and
liver metastases);
* Serum total bilirubin <=1.5 x institutional ULN (total bilirubin must be
<=3.0 x institution*s ULN in subjects with Gilbert*s syndrome). Serum total
bilirubin
<=3.0 x institutional ULN for subjects with CCC and liver metastasis;
* For Parts B, C, D only:
o Hemoglobin * 9.0 g/dL (without transfusion within 30 days of Cycle 1
Day 1);
o AST, ALT, and alkaline phosphatase (ALP) <=2.5 × institution*s ULN (without
exemption for liver or bone metastases);
o International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) <=1.5 × ULN (unless subject is on therapeutic anticoagulation, at which
time the INR and aPTT must be in the target therapeutic anticoagulation
range); and
o Serum albumin >=2.5 g/dL.

9. Women of childbearing potential (defined as women who have experienced
menarche and
who are not permanently sterile or postmenopausal; postmenopausal is defined as
12 consecutive months with no menses without an alternative medical cause) and
males must
agree to use a highly effective method of contraception prior to study entry,
while on study
drug, and for a period of 50 days after the last dose of CX-2009
or 6 months after the last dose of C

Subjects who fulfill any of the following criteria at Screening will not be
eligible for admission:

1. Neuropathy >Grade 1;

2. Active or chronic corneal disorder, including but not limited to the
following: Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment),
history of corneal transplantation, active herpetic keratitis, and also active
ocular conditions requiring ongoing treatment/monitoring such as wet
age-related macular degeneration requiring intravitreal injections, active
diabetic retinopathy with macular edema, presence of papilledema, and acquired
monocular vision;
3. Serious concurrent illness, including, but not limited to the following:

• Clinically relevant active infection including known active hepatitis B or
C, human immunodeficiency virus infection, or cytomegalovirus infection or any
other known concurrent infectious disease, requiring IV antibiotic, antiviral,
or antifungal therapy within 2 weeks of study enrollment;
• History of or current active autoimmune diseases, including but not
limited to myasthenia gravis, inflammatory bowel diseases, rheumatoid
arthritis, autoimmune thyroiditis which is not a sequela of prior immune
checkpoint therapy, autoimmune hepatitis, systemic sclerosis, systemic lupus
erythematosus, autoimmune vasculitis, autoimmune neuropathies, or type 1
insulin dependent diabetes mellitus;
• Significant cardiac disease such as recent myocardial infarction (£6
months prior to
Day 1), unstable angina pectoris, uncontrolled congestive heart failure (New
York Heart Association >class II), uncontrolled hypertension (NCI CTCAE v4.03
Grade 3 or higher), uncontrolled cardiac arrhythmias, severe aortic stenosis,
or ³Grade 3 cardiac toxicity following prior chemotherapy;
• History of multiple sclerosis or other demyelinating disease,
Eaton-Lambert syndrome
(para-neoplastic syndrome), history of hemorrhagic or ischemic stroke within
the last
6 months, or alcoholic liver disease;
• Non-healing wound(s) or ulcer(s) except for ulcerative lesions caused by
the underlying neoplasm;
• Psychiatric illness/social situations that would limit compliance with
study requirements;
or
• Interstitial lung disease irrespective of etiology;

4. Advanced or metastatic Stage IV NSCLC subjects with EGFR or ALK genomic
alterations unless they have progressed on treatment with appropriate targeted
therapy, including osimertinib for T790M mutation-positive NSCLC;
5. Any other anticancer treatment such as chemotherapy, immunotherapy,
biochemotherapy, radiotherapy, investigative therapy, or high-dose steroids
within 30 days of receiving study drug. Low-dose steroids, luteinizing
hormone-releasing hormone, aromatase inhibitors
(eg, anastrozole), at doses that have been stable for ³30 days are permitted
for subjects with
CRPC;

6. History of severe allergic or anaphylactic reactions to previous mAb
therapy;

7. Prior treatment with maytansinoid-containing drug conjugates (eg, Kadcyla
[T-DM1]);

8. Subjects with a previously documented absence of thiol-S-purine
methyltransferase activity;

9. Unresolved acute toxicity NCI CTCAE v4.03 Grade >1 (or baseline, whichever
is greater)
from prior anticancer therapy. Alopecia and other nonacute toxicities are
acceptable;

10. History of malignancy that is active within the previous 2 years except for
localized cancers that are not related to the current cancer being treated, are
considered to have been cured and in the opinion of the Investigator, present a
low risk for recurrence, including basal or squamous cell skin cancer,
superficial bladder cancer or carcinoma in situ of the prostate, cervix or
breast;
11. Currently receiving anticoagulation therapy with warfarin;

12. The subject has undergone major surgery (requiring general anesthesia)
within 3 months prior to dosing. Subjects who have undergone major surgery
within this time period may be enrolled, after consultation with the Medical
Monitor;
13. Subjects who have received a live vaccine within 28 days prior to the
planned first dose of CX-2009 (examples include, but are not limited to, the
following: measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies,
Bacillus Calmette-Guérin, and typhoid vaccine);
14. Participating in an ongoing clinical study involving treatment with
medications, radiation, or surgery;
15. Women who are pregnant or breast feeding; or

16. Subjects who are >20.0% below their ideal body weight, as determined using
the formula in
Appendix F.

Additional Exclusion Criteria for Parts D1 and D2

17. History of myocarditis regardless of the cause;

18. History of intolerance to prior ICI therapy defined as the need to
discontinue treatment due to an irAE;
19. History of any syndrome or medical condition that requires treatment with
systemic steroids (>=10 mg daily prednisone equivalents) or immunosuppressive
medications. However, subjects who require brief courses of steroids (eg, as
prophylaxis for IV contrast or for treatment of an allergic reaction) may be
eligible with Sponsor approval. Inhaled or topical steroids are permitted;
20. History of allogeneic tissue/solid organ transplant, stem cell transplant,
or bone marrow transplant.