Inclusion Criteria All Parts. 1. Provision of written informed consent prior to any study related procedures and
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol.
2. Male or female patients ≥18 years of age at the time of study entry who agree to
participate by giving written informed consent prior to participation in any study
related activities.
3. Histologically or cytologically confirmed advanced solid tumors, specifically:
Dose Escalation for Part A may include:
Patients with tumors harboring actionable KEAP1/NFE2L2/STK11/NF1 mutations Patients
with low ASNS expression levels (HGSOC or endometrial cancer) Patients who had
immunotherapy (IO) melanoma (Minimum treatment duration of prior PD-1 or
PD-L1-containing regimen of 12 weeks [or equivalent of 2 response evaluations]).
Patients with post-platinum HNSCC Patients with chondrosarcoma Patients with ARID1A
mutant clear cell ovarian cancer. Dose Escalation for Part B may include:
Confirmed recurrent high-grade non-mucinous ovarian cancer that is platinum-resistant,
defined as disease relapse within a platinum-free interval (PFI, or the time elapsed
from the last date of platinum dose until PD) of < 6 months, and with less than 5
prior therapies. Dose Expansion for Part B limited to:
Confirmed recurrent high-grade non-mucinous ovarian cancer with low ASNS expression
levels that is platinum-resistant, defined as disease relapse within a PFI of < 6
months, and with less than 5 prior therapies.
Dose Escalation for Part C may include:
Patients with tumors harboring actionable KEAP1/NFE2L2 mutations Patients with tumors
harboring PIK3CA hotspot mutations, activating AKT mutations, and inactivating PTEN
mutations (irrespective of KEAP1/NFE2L2 mutations) Patients with low ASNS expression
levels (HGSOC)
Dose Expansion for Part C limited to:
Patients with NSCLC with actionable KEAP1/NFE2L2 mutations Patients with HGSOClow ASNS
expression levels (irrespective of biomarker status for KEAP1/NFE2L2)
4. Patients must have received at least one line of therapy for advanced stage disease
and be refractory or ineligible to available existing therapy(ies) known to provide
clinical benefit for their condition.
5. Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational
therapies must have been completed at least 3 weeks or at least five half lives,
whichever is shorter, before the study drug administration, and all AEs (excluding
alopecia and peripheral neuropathy) have either returned to ≤Grade 1 or stabilized.
Patients with concurrent use of hormonal therapy for non-cancer related conditions
(e.g., hormone replacement therapy) are allowed.
6. Fresh and/or archival tumor tissue from a biopsy obtained between the completion of
the most recent line of treatment until study entry must be available for mutation and
biomarker analysis. If available, archival tumor tissue from the time of initial
diagnosis or the most recent biopsy (archival and/or fresh) will be collected. For
ovarian cancer patients, a fresh biopsy must be collected in addition to archival
tumor tissue. NOTE: No fresh tumor tissue will be required if a previous biopsy
detected the selected mutations for each cohort. In all cases, procedures to obtain
fresh tumor tissue should not put the patient at undue risk, and should only be
performed if the risk is minimal (no greater than 2% risk of serious or severe
complications).
7. Patients must have at least 1 lesion (measurable and/or non-measurable) that can be
accurately assessed at baseline by CT or MRI and is suitable for repeated assessments.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 with no deterioration
over the previous 2 weeks prior to baseline or day of first dosing.
9. Adequate organ function as indicated by the following laboratory values:
Absolute neutrophil count (ANC) ≥1.0×109/L Platelets ≥100×109/L Hemoglobin ≥9.0 g/dL
(>5.59 mmol/L) Creatinine clearance (CrCl) >50 mL/min. Actual body weight should be
used for calculating creatinine clearance using the Cockroft Gault equation (except
for patients with body mass index >30 kg/m2 when the lean body weight should be used,
and without the need for chronic dialysis therapy).
Serum total bilirubin ≤1.5×ULN (with the exception of patients with known thalassemia
minor mutations or Gilbert's syndrome: serum total bilirubin must be <3×ULN in these
patients) Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and
alanine aminotransferase (serum glutamic pyruvic transaminase) ≤2.5×ULN or ≤5×ULN for
patients with liver metastases)
10. Adequate cardiac function with a left ventricular ejection fraction ≥50%
11. Female patients of non childbearing potential, who are physiologically incapable of
becoming pregnant, are eligible to enter and participate in the study if they:
have had a hysterectomy, OR have had a bilateral oophorectomy, OR have had a bilateral
salpingectomy, OR is postmenopausal (total cessation of menses for ≥2 years, or
follicle stimulating hormone ≥50 IU/L).
12. Female patients of childbearing potential, who are not post-menopausal or surgically
sterile and intent to be sexually active with a non-sterile male partner, are required
to use one form of highly effective contraception combined with a barrier method (male
condom, female condom, cervical cap, diaphragm with spermicide, or contraceptive
sponge with spermicide) of contraception starting before entering the study and until
4 weeks after the last dose of treatment.
Highly effective non-hormonal contraceptive methods that are acceptable include:
Total/true abstinence*** for the total duration of the study treatment and for at
least 1 month after the last dose of study treatment. Periodic abstinence using
methods such as calendar ovulation, symptothermal, post ovulation methods, declaration
of abstinence solely for the duration of a trial, or withdrawal are not acceptable
methods of contraception.
Having a vasectomized sexual partner, who received post-vasectomy confirmation of
azoospermia, combined with a barrier method as described above.
Bilateral tubal occlusion combined with a barrier method as described above.
Intrauterine device with copper banded coils, combined with a barrier method as
described above.
Highly effective hormonal contraceptive methods that are acceptable include:
Combined oral pill contraception (normal and low-dose oral pills, or
progesterone-based oral pills using desogestrel) combined with a barrier method as
described above. NOTE: cerazette is currently the only highly efficacious
progesterone-based pill available.
Injection (e.g., medroxyprogesterone) combined with a barrier method as described
above.
Patch (e.g., norelgestromin or ethinyl estradiol transdermal system) combined with a
barrier method as described above.
Implants (etonorgestrel-releasing) combined with a barrier method as described above.
Intravaginal device (e.g., ethinyl estradiol- or etonogestrel-releasing) combined with
a barrier method as described above.
Intrauterine system (levonorgestrel-releasing) combined with a barrier method as
described above.
In addition to the to use one form of highly effective contraception combined with a
barrier method, female patients of childbearing potential must have a negative serum
pregnancy test at screening (within 7 days of the start of treatment) and must not be
breastfeeding.
13. Non-sterile men, who are not sexually abstinent and intend to be sexually active with
a woman of childbearing potential, must use a condom from the start of the trial and
until 16 weeks after the last dose of treatment, or must practice total abstinence***
for the total duration of the study treatment and at least 3 months after the last
dose of study treatment. Periodic abstinence, the rhythm method, and the withdrawal
method are not acceptable methods of contraception. Female partners of childbearing
potential should consider the use of at least one contraception method describe above.
If the female partner is pregnant, male participants should use a condom plus
spermicide.
- - Total/true abstinence is defined as a patient who refrains from any form of
sexual intercourse, and this is in line with their usual and/or preferred
lifestyle.
Exclusion Criteria All Parts. 1. Prior malignancy within the previous 2 years except for locally curable cancers that
have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of
the cervix, breast or bladder.
2. Known primary central malignancy or symptomatic central nervous system metastasis(es).
Note: Patients with stable, previously treated brain metastases may participate if
neurologic symptoms have resolved, patients have been off steroids (at least 7 days
for Part A and Part B, and at least 4 weeks for Part C), and there is no evidence of
disease progression by imaging for at least 2 weeks before the first dose of study
treatment.
3. Uncontrolled, significant intercurrent or recent illness including, but not limited
to, the following cardiac conditions:
1. Any unstable cardiac arrhythmia within 6 months prior to enrolment. 2. Prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 ms
for males and >470 ms for females. 3. History of any of the following cardiovascular conditions within 6 months of
enrolment:
- - cardiac angioplasty or stenting, myocardial infarction, unstable angina,
coronary artery bypass graft surgery, symptomatic peripheral vascular
disease, class III or IV congestive heart failure, as defined by the New
York Heart Association.
4. Major surgical intervention within 28 days before study drug administration, or an
anticipated need for major surgery during the study.
5. Significant acute or chronic infections.
6. Any psychiatric condition that would prohibit the understanding or rendering of
informed consent.
7. Treatment with strong cytochrome P450 subtype 3A4 (CYP3A4) inducers and inhibitors
(including grapefruit juice) within 2 weeks of the first dose of study drug NOTE:
patients must have stopped taking St. John's Wort 3 weeks prior to the start of
treatment and stopped taking enzalutamide 4 weeks prior to the start of treatment.
8. Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors or sensitive CYP3A4
substrates within 7 days of the first dose of study drug.
9. Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy
for symptomatic control is acceptable if completed at least 2 weeks prior to study
drug administration and no additional radiotherapy for the same lesion is planned.
10. Underlying medical conditions (such as severe or uncontrolled systemic diseases,
including uncontrolled hypertension, renal transplant and active bleeding diseases),
for which in the investigator's opinion will make the administration of study drug
hazardous or obscure the interpretation of toxicity determination or AEs.
11. History of allergic reactions attributed to compounds of similar chemical or
biological composition to any of the compounds in the study.
12. Known history of alcohol or drug abuse.
13. Legal incapacity or limited legal capacity.
14. Inability to swallow oral medications (capsules and tablets) without chewing,
breaking, crushing, opening or otherwise altering the product formulation. Patients
should not have gastrointestinal illnesses (such as refractory nausea and vomiting,
chronic gastrointestinal disease or previous significant bowel resection that would
preclude adequate absorption, distribution, metabolism, or excretionof IACS-6274 and
capivasertib, which are oral agents.
15. Patients unwilling to comply with protocol requirements related to the assigned part.
16. Any other disease, physical examination finding, or clinical laboratory finding that,
in the investigator's opinion, gives reasonable suspicion of a disease or condition
that contraindicates the use of an investigational drug, may affect the interpretation
of the results, render the patient at high risk from treatment complications or
interferes with obtaining informed consent.
Part B Specific Exclusion Criteria (B1) Known severe hypersensitivity reactions to
monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three
or more features of partially controlled asthma).
(B2) Patient has a known hypersensitivity to paclitaxel or bevacizumab components or
excipients.
(B3) Patient has a history of bowel obstruction, including sub-occlusive disease, related
to the underlying disease and history of abdominal fistula, gastrointestinal perforation,
or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic examination
or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
(B4) Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at
screening or urine dipstick for proteinuria ≥2 (patients discovered to have ≥2 proteinuria
on dipstick at baseline should undergo 24-hour urine collection and must demonstrate <2 g
of protein in 24 hours to be eligible).
(B5) Patient is at increased bleeding risk due to concurrent conditions (e.g., major
injuries or surgery within the past 28 days prior to start of study treatment, history of
hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically
significant hemorrhage within the past 3 months).
(B6) Patient has clinically significant cardiovascular disease (e.g., significant cardiac
conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac
arrhythmia or unstable angina, New York Heart Association Grade 2 or greater congestive
heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater
peripheral vascular disease, and history of cerebrovascular accident [CVA]) within 6 months
of enrollment. (B7) Patient has pre-existing peripheral neuropathy that is Grade ≥2 by
Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria.
(B8) Patient requires paracentesis 2 weeks prior to trial enrolment. Part C Specific
Exclusion Criteria (C1) History of another primary malignancy, except for a malignancy
treated with curative intent, with no known active disease ≥5 years before the first dose
of treatment, with low potential risk for recurrence. Exceptions include basal cell
carcinoma of the skin and squamous cell carcinoma of the skin that has undergone
potentially curative therapy.
(C2) Patient has a known hypersensitivity to capivasertib components or any excipients of
the product.
(C3) Clinically significant abnormalities of glucose metabolism as defined by any of the
following: Diagnosis of diabetes mellitus type I or II (irrespective of management),
Glycosylated haemoglobin (HbA1c) >8% (64 mmol/mol) (C4) Patients with evidence of severe or
uncontrolled systemic liver disease including severe hepatic impairment, or abnormal liver
enzymes at screening (AST or ALT >2.5 x ULN; total bilirubin >1.5 x ULN).
(C5) Patients with elevated alkaline phosphatase (ALP) can be enrolled if the abnormal
value is due to the presence of bone metastasis, but liver function is considered adequate
according to the principal investigator.
(C6) Patients with persistent toxicities (Grade ≥2 by Common Terminology Criteria for
Adverse Events (CTCAE) version 4) caused by previous anticancer therapy, excluding
alopecia. Participants with irreversible toxicity that is not reasonably expected to be
exacerbated by study treatment may be included after consultation with the sponsor and the
study physician.
(C7) Patients with spinal cord compression or leptomeningeal disease not requiring steroids
for at least 4 weeks prior to start of study intervention.
(C8) Patients with clinically significant cardiovascular disease including, but not limited
to, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial
infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 2 or
greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2
or greater peripheral vascular disease, and history of cerebrovascular accident [CVA])
within 6 months of enrollment. In addition, patients will be excluded based on the study
physician's judgment of the following criteria:
- - Mean resting corrected QT interval >470ms, obtained from triplicate ECGs performed at
screening.
- - Medical history significant for arrhythmia that is symptomatic or requires treatment
(CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation regardless of
treatment, or asymptomatic sustained ventricular tachycardia.
Participants with atrial
fibrillation controlled by medication or arrhythmias controlled by pacemakers may be
included based on the study physician's judgment.
- - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalemia of Grade ≥1, potential for Torsades de Pointes,
congenital long QT syndrome, family history of long QT syndrome or unexplained sudden
death under 40 years of age in first-degree relative, history of QT prolongation
associated with other medications that required discontinuation of the medication.
- - Experience of any of the following procedures or conditions in the preceding 6 months:
coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction,
angina pectoris, congestive heart failure New York Heart Association Grade ≥2.
- - Uncontrolled hypotension: SBP <90 mmHg and/or DBP <50 mmHg.
- - Cardiac ejection fraction outside institutional range of normal or <50% (whichever is
higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an
echocardiogram cannot be performed or is inconclusive).
(C9) Patients with active tuberculosis infection (clinical evaluation that may include
clinical history, physical examination and radiographic findings, or tuberculosis testing
in line with local practice) are excluded.
(C10) Patients with active hepatitis infection, positive hepatitis C antibody, hepatitis B
virus surface antigen or hepatitis B virus core antibody, at screening are excluded.
Human immunodeficiency virus (HIV) positive patients with a viral load > 400 copies/mL and
a CD4+ T-cell count of <350 cells/uL or with a history of an acquired immunodeficiency
syndrome (AIDS) opportunistic infection within the past 12 months are excluded. Patients
with a higher viral load or lower CD4+ count (< 350 cells/uL) may be considered for
eligibility if the patient has a potentially curable malignancy or for interventions in a
later stage of development that have demonstrated prior activity with a given cancer.
HIV-positive patients receiving antiretroviral therapies should be on established ART for
at least four weeks before starting treatment to ensure that treatment is tolerated and
that toxicities are not confused with investigational drug toxicities. HIV-positive
patients receiving antiretroviral therapies that are strong CYP3A4/5 inhibitors/ inducers
or sensitive substrates of CYP3A4 will be excluded due to the potential for drug-drug
interaction with capivasertib.
(C12) Patients who are undergoing any concurrent anticancer treatment or any concomitant
medication that may interfere with the study drugs according to local clinical guidelines
are excluded.
(C13) Patients who received palliative radiotherapy within 2 weeks prior to the start of
study treatment; or radiotherapy to more than 30% of the bone marrow within 4 weeks before
the start of study treatment are excluded.
