This study will evaluate the effect of fluconazole and isavuconazole on the PK of acalabrutinib and its active metabolite, ACP-5862.

This is a 2-period study. On Day 1 of Period 1, all participants will be randomized to 1 of 2 treatment sequences and will receive a single oral dose of 100 mg acalabrutinib (Treatment A). In Period 2, the participants who participated in Period 1 will receive either Treatment B (fluconazole) or Treatment C (isavuconazole). In Period 2 Treatment B, participants will receive a single oral loading dose of 400 mg fluconazole on Day 1 one hour before a single oral dose of 100 mg acalabrutinib. In Period 2 Treatment C, participants will receive oral dose of 200 mg isavuconazole three times daily (TID; approximately 8 hours apart) on Day 1 and 200 mg isavuconazole once daily (QD) from Day 2 to Day 5 with a single oral dose of 100 mg acalabrutinib coadministered on Day 5. There will be a washout of at least 8 days between Period 1 and first dose in Period 2. All participants will return to the study site approximately 7 days after the last study drug for follow-up procedures and adverse event.

Inclusion Criteria:

• Continuous non-smoker participant who has not used nicotine-containing products for at least 3 months prior to the first dosing and throughout the study
• Have body mass index of >= 18 kg/m^2 and <= 32 kg/m^2 at screening
• Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or ECGs, as deemed by the principal investigator (PI)
• Women participants must be of non-childbearing status and must have undergone the protocol specified sterilization procedures, and have official documentation, at least 6 months prior to the first dose; or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle-stimulating hormone serum levels consistent with postmenopausal status
• Male participants must be willing to use protocol specified contraception methods
• Male participants must agree not to donate sperm from the first dosing until 90 days after the last dosing
• Ability to swallow multiple capsules and/or tablets using size 0 blank capsules (up to a maximum of 3 capsules per participant)

Exclusion Criteria:

• Participant is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study

• History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee

• History of any illness that, in the opinion of the PI, might confound the results of the study or poses an additional risk to the participant by their participation in the study

• Presence of any clinically significant, ongoing systemic bacterial, fungal, or viral infections (including upper respiratory tract infections, but excluding localized cutaneous fungal infections), in the opinion of the PI

• History of any major surgical procedure within 30 days before the first dose of study drug

• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing

• History or presence of clinically significant hypersensitivity or idiosyncratic reaction to acalabrutinib, fluconazole, isavuconazole, related compounds, or any inactive ingredients

• History or presence of liver disease and diabetes mellitus

• History of stroke or intracranial hemorrhage within 6 months before the first dosing

• History of bleeding diathesis

• Any clinically significant condition that may affect acalabrutinib absorption in the opinion of the PI, including gastric restrictions and bariatric surgery (eg, gastric bypass). Participants with cholecystectomy will be allowed.

• QTcF interval is >460 msec (males) or >470 msec (females) or has ECG findings deemed abnormal with clinical significance by the PI or designee at screening

• Women who are pregnant or lactating

• Positive urine drug or alcohol results at screening or first check-in

• Positive urine cotinine at screening

• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), or hepatitis C virus (HCV)

• Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening

• Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening

• Estimated creatinine clearance <90 mL/min and hemoglobin level below the lower limit of normal at screening

• Have been on a diet incompatible with the on-study diet, in the opinion of the PI, within the 28 days prior to the first dose of study drug, and throughout the study

• Donation of blood or significant blood loss within 56 days and plasma donation within 7 days prior to the first dose of study drug

• Unable to refrain from or anticipates the use of:

  • Any drugs, including prescription and nonprescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to the first dose and throughout the study
  • Any drugs known to be significant inducers or inhibitor of Cytochrome P450 (CYP) enzymes and/or P-glycoprotein (P-gp), including St. John's Wort, for 28 days prior to the first dose of study drug and throughout the study, including drugs with a narrow therapeutic window that are P-gp substrates such as digoxin.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.