| Eligibility |
Inclusion Criteria:
1. Have a signed an informed consent form prior to any study specific procedures or
treatment
2. Be =18 years of age (male or female) at the time of consent
3. Phase 1a:
Have 1 of the following tumor types with qualifying characteristics, and have received
at least 1 and no more than 5 prior lines of therapy for metastatic (stage IV)
disease:
1. SCCHN
2. CRC
3. NSCLC
4. TCC
5. Other solid tumors (eg, carcinoma of unknown primary) with the exception of
rapidly progressing neoplasms (eg, pancreatic cancer, glioblastoma,
hepatocellular carcinoma). Note: Subjects do not need to have progressed through
all possible available therapies with known clinical benefit for their respective
cancers to participate in this study. Note: Subjects with SCCHN, CRC, NSCLC, and
TCC are a priority and should constitute as a whole, at least 50% of the enrolled
population. Enrollment of all others will be capped when reaching a combined 50%,
in order to maintain 18 slots for subjects with SCCHN, CRC, NSCLC, and TCC.
Phase 1b:
Have renal cell carcinoma with respective qualifying characteristics:
1. Histological or cytological proof of component (any percentage) of clear cell
RCC, excluding subjects that have any component of collecting duct or medullary
histology are eligible
2. Subjects with residual, but well-controlled endocrinopathy (eg, hypothyroidism)
are eligible
3. Subjects with metastatic or locally advanced unresectable RCC Note: Prior
nephrectomy is not mandatory.
4. Subjects with progressive disease after receipt of at least 2 and no more than 5
prior lines of therapy for metastatic (stage IV) disease, including but not
limited to VEGF-directed tyrosine kinase inhibitors (TKIs), high-dose IL-2 ,
immune checkpoint inhibitors, mTOR inhibitors, or belzutifan, alone or in
combination. Note: A line of therapy is considered complete once the patient has
progressed following such treatment. If a treatment regimen is changed before
disease progression due to toxicity, for example, this is still considered part
of the same line of therapy. In addition, maintenance therapy [that is, therapy
with a different drug or drugs given to conserve an existing response or stable
disease before disease progression] is not considered an additional line of
therapy.
4. Have at least 1 radiologically measurable lesion as per Response Evaluation Criteria
in Solid Tumors (RECIST) v 1.1 defined as a lesion that is at least 10 mm in longest
diameter or lymph node that is at least 15 mm in short axis imaged by CT scan or
magnetic resonance imaging and obtained by imaging within 28 days prior to study
treatment. Tumor lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions
5. Have resolution of all previous treatment related toxicities to Grade 1 severity or
lower, except for stable sensory neuropathy (=Grade 2) and alopecia. If the subject
received major surgery or radiation therapy of >30 Gy, they must have recovered from
the toxicity and/or complications from the intervention
6. If subjects were previously treated with immune checkpoint inhibitors, at least 4
weeks must have elapsed since the last dose, and they must have recovered from
toxicities as mentioned in above Criterion #5
7. Subjects must have at least one biopsiable lesion at baseline. Biopsies in this
clinical study will conform to American Society of Clinical Oncology's Ethical
Framework for Including Research Biopsies in Oncology Clinical Trials. Provided there
are suitable and accessible lesions, no biopsy contraindications, minimal risk of
complications and a positive informed decision, subjects are willing to provide fresh
tissue for biomarker analysis, and, based on the adequacy of the tissue sample
quality, for assessment of biomarker status. Two biopsies will be necessary: at
baseline (within 15 days prior to study Day 1) and at the time of the first response
assessment CT scan at Cycle 3/Day 1 (+7 days). Newly obtained biopsy specimens are
preferred to archived samples and formalin fixed, paraffin embedded block specimens
are preferred to slides. Biopsies should not be taken from target lesions
8. Have Eastern Cooperative Oncology Group performance status of 0 or 1 and sustained
between screening and initiation of dosing on Day 1
9. Have no swallowing difficulties that would prevent compliance with oral dosing
10. Have not experienced >10% body weight loss in the previous 4 weeks
11. Have a serum albumin level >3 g/dL
12. Have life expectancy of 3 months or greater as determined by the treating physician
13. Have adequate organ function on Day 1, as defined by meeting all of the following
criteria:
1. Total bilirubin =1.5 × upper limit of normal (ULN) OR direct bilirubin =ULN for
subjects with total bilirubin levels >1.5 x ULN
2. Aspartate aminotransferase and alanine aminotransferase =2.5 × ULN or =5 × ULN
for subjects with known hepatic metastases
14. Have adequate renal function on Day 1, as defined by creatinine =1.5 × ULN and
creatinine clearance =60 mL/min, as per the below Cockcroft Gault formula
15. Have adequate hematologic function on Day 1, as defined by meeting all of the
following criteria:
1. Hemoglobin =9 g/dL (uncorrected by red blood cell transfusion or erythropoietin
support)
2. Absolute neutrophil count =1.5 × 109/L
3. Platelet count =100 × 109/L
16. Have adequate coagulation function on Day 1, as defined by either of the following
criteria:
1. International normalized ratio (INR) <1.5 × ULN OR for subjects receiving
warfarin or low molecular weight heparin, the subject must, in the investigator's
opinion, be clinically stable with no evidence of active bleeding while receiving
anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is
the goal of anticoagulant therapy
2. Activated partial thromboplastin time <1.5 × ULN unless subject is receiving
anticoagulant therapy, provided prothrombin time or partial thromboplastin time
is within therapeutic range of intended use of anticoagulants
17. Have normal or adequately controlled pan-endocrine function (pituitary, adrenal,
thyroid, pancreatic, gonadal). Subjects on hormonal supplementation must be stable at
their treatment doses
18. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required
19. Female subjects of childbearing potential must be willing to use an adequate form of
contraception from the signing of the ICF until 90 days after the last dose of study
medication
20. Female subjects must agree not to breastfeed and not to donate ova starting at
screening and throughout the study treatment, and for 90 days after the final
administration of study drug
21. Male subjects with a pregnant or breastfeeding partner(s) must agree to remain
abstinent or use a condom for the duration of the pregnancy or for the time their
partner is breastfeeding throughout the study treatment and for 90 days after the
final administration of study drug
22. Male subjects must not donate sperm during the treatment period and for at least 90
days after the final administration of the study drug
23. Male subjects with female partner(s) of child bearing potential must agree to use a
condom with spermicide during the treatment period and for at least 90 days after the
final administration of the study drug
24. Be willing and have the ability to comply with scheduled visits (including
geographical proximity), treatment plans, laboratory tests, and other study
procedures.
Exclusion Criteria:
1. Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
weeks prior to the first dose of study treatment or who has not recovered from adverse
reactions due to a previously administered agent or major surgery
2. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment
3. Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment. The use of physiologic doses of corticosteroids may be approved after
consultation with the sponsor
4. Has known history of active tuberculosis
5. Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
6. Has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C
(eg, hepatitis C virus ribonucleic acid [RNA] [qualitative]) infection
7. Has been diagnosed with any infectious process that would, in the opinion of the
investigator, interfere with study participation, especially regarding site-specific
testing and isolation requirements. This applies to viral infections including, but
not limited to, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection
8. Has a history of clinically severe autoimmune disease, or history of organ transplant
9. Has a history of retinitis or photosensitive skin disorders including (but not limited
to) erythema multiforme, atopic eczema, psoriasis, viral exanthemata, pemphigus, and
dermatitis herpetiformis
10. Has known additional malignancy that is progressing or required active treatment
within the previous 5 years. Exceptions include basal cell carcinoma or squamous cell
carcinoma of the skin that has undergone potentially curative therapy, superficial
bladder cancer, or in situ cervical cancer. Subjects with other malignancies are
eligible if they were cured by surgery alone or surgery plus radiotherapy and have
been continuously disease free for at least 5 years
11. Has known active central nervous system metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of disease progression by imaging for at least 4 weeks prior
to the first dose of study treatment and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
systemic steroids for at least 7 days prior to study treatment. This exception does
not include carcinomatous meningitis which is excluded regardless of clinical
stability
12. Has a history of interstitial lung disease, pneumonitis within 12 months prior to
screening, or current pneumonitis
13. Has an active infection requiring systemic therapy
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
15. Has a clinically significant cardiovascular disease such as unstable angina,
myocardial infarction, or acute coronary syndrome, symptomatic or uncontrolled
arrhythmia, congestive heart failure, baseline electrocardiogram (ECG) abnormalities,
including, but not limited to, QTc prolongation (as calculated using Fridericia
formula) to greater than 450 ms for males or to greater than 470 ms for females, or
any Class III or IV cardiac disease as defined by the New York Heart Association
Functional Classification
16. Has overt or latent disorders of the exocrine pancreas (such as acute or chronic
pancreatitis of any etiology) or chronic (including autoimmune) gastrointestinal
disorders such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, lupus,
scleroderma, Sjogren's syndrome, and polyarteritis nodosa
17. Has a known psychiatric or substance abuse disorder(s) that would interfere with
informed consent or cooperation with the requirements of the study
18. Is pregnant or breastfeeding or expecting to conceive children within the projected
duration of the study, starting with the screening visit through 90 days after the
final administration of the study drug
19. Is a first degree relative of the investigator, staff, or study sponsor.
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