This a two-arm, non-randomized phase 1/1B trial aiming at assessing the safety and activity
of abemaciclib alone (arm 1), and abemaciclib plus MK-6482 (arm 2) in patients with advanced
refractory clear-cell renal cell carcinoma (croc).
A Phase I clinical trial tests the safety of an investigational drug or drug combination and
also tries to define the appropriate dose of the investigational drug or drug combination to
use for further studies. "Investigational" means that the drug is being studied.The U.S. Food
and Drug Administration (FDA) has not approved either abemaciclib or MK-6482 for renal
(kidney) cancer but abemaciclib has been approved to treat other forms of cancer.
Abemaciclib is in a class of drugs known as CDK4 & 6 inhibitors. These proteins control how
fast cells grow and divide and are found on both normal and cancer cells. They become
overactive in cancer cells causing cells to grow and divide uncontrollably. Abemaciclib
blocks these proteins just as the cells start to grow and divide and in other cancers has
been shown to slow down cancer cell growth and division, causing cancer cells to become
inactive or even die.
MK-6482 is an oral, first-in-class selective small-molecule inhibitor that targets
hypoxia-inducible factor (HIF)-2a, which promotes the growth of new vessels that fuel kidney
cancer.
This study is looking at two different treatments:
- Arm 1 - abemaciclib alone:
- To determine the response rate of abemaciclib alone in patients with advanced ccRCC
- Arm 2 - combination therapy of abemaciclib and MK-6482
- To determine the maximum dose of abemaciclib and MK-6482 in combination.
- To determine the response rate of abemaciclib and MK-6482 in patients with advanced
ccRCC.
The research study procedures include screening for eligibility, study treatment, participant
evaluations and safety follow-up visits, in addition to general health status follow-up after
study treatment. It is estimated that participants will receive 12 to 18 months of study
treatment and 3 months of safety follow-up, totaling about 15 to 21 months from the start of
study treatment. After the safety follow-up visits, the study doctor may request that
participants return to clinic for additional tumor assessments or his/her staff will contact
participants about every 6 months to follow their health status and find out about any
anticancer treatments participants may have begun after study treatment.
It is expected that about 40 people will take part in this research study.
The pharmaceutical company Eli Lilly is supporting this research study by providing funding
for the research study, tests required for research purposes only, and the study drugs. The
pharmaceutical company Merck is supporting this research study by providing study drug.
Inclusion Criteria:
- Histologically or cytologically confirmed unresectable advanced or metastatic renal
cell carcinoma with clear cell component. Patient with extensive sarcomatoid histology
are accepted.
- Participants must have failed at least 1 prior anti-VEGFR systemic therapy and 1
immune checkpoint inhibitor for metastatic RCC. No limit on the number of prior lines
of therapies.
- Measurable disease as per RECIST 1.1. See section 12 for the evaluation of measurable
disease.
- Age ≥ 18 years
- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
- Participants must undergo fresh tumor biopsy unless medically unsafe or not feasible.
- Normal organ and marrow function as defined below:
- Absolute neutrophil count ≥1,500/mcL
- Platelets ≥100,000/mcL
- Hemoglobin ≥10g/dL (transfusions allowed)
- Total bilirubin ≤2.0 x institutional upper limit of normal with the
following exception: patients with known Gilbert disease should have a serum
bilirubin ≤ 3 x ULN
- AST(SGOT)/ALT(SGPT)≤3.0 × institutional upper limit of normal with the
following exception: patients with known liver metastases should have AST
and ALT
≤ 5 x ULN
- Creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault
equation. (APPENDIX F)
- Urine protein/creatinine ratio (UPC ratio) ≤2
- Women of child-bearing potential and men must agree to use adequate contraception
(intrauterine device or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation and 6 months after completion
abemaciclib plus MK- 6482 and at least 3 weeks after the completion of abemaciclib
administration. If condoms are used as a barrier method, a spermicidal agent should be
added as a double barrier protection. A negative pregnancy serum test should be
obtained within 7 days of therapy initiation. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
to be collected for regulatory reporting and drug safety evaluation.. 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 6 months after completion
abemaciclib plus MK-6482 and at least 3 weeks after the completion of abemaciclib
administration.
- Ability to swallow oral medications
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
A patient will be excluded from the study if he or she meets any of the following criteria:
- Patients receiving any other investigational agents.
- Patients who received prior CDK4/6 inhibitors.
- For Arm 2 only, patients who have received prior HIF-2α inhibitor.
- Participants who have received any continuous or intermittent small molecule
therapeutics (excluding monoclonal antibodies) ≤ 4 effective half-lives prior to
starting study drug or who have not recovered from side effects of such therapy to
grade 1 or less (except for non-clinically significant laboratory abnormalities).
- Patients must have discontinued all biologic therapy including therapeutic antibodies
at least 28 days before C1D1.
- Participants who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy to at least grade 1.
- Participants with untreated brain metastases are excluded. However, participants with
metastatic ccRCC to the brain may participate in this trial, if the participant is ≥ 4
weeks from therapy completion (incl. radiation and/or surgery), is clinically stable
at the time of study entry and is not receiving corticosteroid therapy >10 mg/day
prednisone or equivalent. A repeat MRI or CT Brain to show stability is required
- O2 saturation <92% by arterial blood gas analysis or pulse oximetry on room air
- Untreated deep vein thrombosis or pulmonary embolism, or event of deep vein thrombosis
or pulmonary embolism within 2 weeks of treatment start. Patient should be on at least
1 week of anticoagulation before C1D1.
- The patient has serious and/or uncontrolled preexisting medical condition(s) that, in
the judgment of the investigator, would preclude participation in this study (for
example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],
history of major surgical resection involving the stomach or small bowel, or
preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition
resulting in baseline Grade 2 or higher diarrhea)."
- Patient with active systemic bacterial infection (requiring IV antibiotics at the time
of initiating study treatment), fungal infection, or detectable viral infection.
Patients with known viral infection (such as HIV) are excluded given the potential for
interactions between antiretroviral agents and abemaciclib, and the potential for
increased risk of lifethreatening infection with therapy that is myelosuppressive. If
you are not known to have HIV, a HIV test is required.
- Patients with known Hepatitis B or Hepatitis C infection are excluded only if there is
evidence of active infection (detectable Hepatitis B surface antigen, detectable
Hepatitis C RNA).
- Prior allogenic stem cell or solid organ transplant.
- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of oral drugs (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection).
- Participants who have undergone major surgery ≤ 4 weeks (28 days) prior to starting
study drug(s) or who have not recovered from side effects of such therapy.
- Participants who are currently taking therapeutic doses of warfarin sodium or any
other coumadin-derivative anticoagulant.
- Other malignancy diagnosed within 2 years of first study treatment unless negligible
risk of metastases or death according to the investigator (included but not limited to
carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized
prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive
urothelial carcinoma, or other malignancy not deemed to impact patients 5-year life
expectancy).
- Has a personal history of any of the following conditions: syncope of cardiovascular
etiology, ventricular arrhythmia of pathological origin (including, but not limited
to, ventricular tachycardia and ventricular fibrillation), sudden cardiac arrest.
- Has had any major cardiovascular event within 6 months prior to study drug
administration iincluding but not limited to: myocardial infarction, unstable angina,
cerebrovascular accident, transient ischemic event or New York Heart Association Class
III or IV heart failure. Patients with history of DVT or PE are eligible provided DVT
or PE occurred at least 2 weeks prior to C1D1 and anticoagulation has been initiated
at least 1 week before C1D1.
- History of symptomatic respiratory condition considered clinically significant by the
investigator. History of asymptomatic radiation pneumonitis within a previous
radiation field is permitted.
- Participants with a known hypersensitivity to the study compounds or to its
excipients.
- Participant is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator
- Females that are pregnant or lactating
- Participants who have taken herbal medications and certain fruits within 7 days prior
to starting study drug. Herbal medications include, but are not limited to St. John's
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe,
saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville oranges,
grapefruit, pommelos.
