AzTrials
AzTrials

Acute Myeloid LeukemiaPhase 1NCT04659616

Pemigatinib After Chemotherapy for the Treatment of Newly Diagnosed Acute Myeloid Leukemia

A Phase 1 study testing Biospecimen Collection, Bone Marrow Aspirate and Bone Marrow Biopsy in people with Acute Myeloid Leukemia, run by OHSU Knight Cancer Institute at 2 sites in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

This phase I trial identifies the best dose and clinical benefit of giving pemigatinib following standard induction chemotherapy in patients with newly diagnosed acute myeloid leukemia. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Myeloid Leukemia
What is being tested?
Biospecimen Collection, Bone Marrow Aspirate and Bone Marrow Biopsy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
2 sitesUnited States
Study dates
14 Jan 2021to 31 Dec 2026
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • PRE-SCREENING INCLUSION CRITERIA: Ability to understand and the willingness to sign a written informed consent document
  • PRE-SCREENING INCLUSION CRITERIA: Age >= 18 years at time of informed consent. Both men and women of all races and ethnic groups will be included
  • PRE-SCREENING INCLUSION CRITERIA: Participants must consent to a bone marrow aspirate/biopsy that will be collected prior to start of planned 7+3 induction therapy. Patients with known favorable risk AML (2022 European Leukemia Net [ELN] Guidelines) or FLT3 mutations should not be pre-screened. If the risk category is unknown, then it is okay to pre-screen patients for study. Adverse or intermediate risk needs to be confirmed prior to treatment with pemigatinib (during screening period) as outlined below
  • TREATMENT INCLUSION CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • TREATMENT INCLUSION CRITERIA: For both the dose-determining and dose-expansion cohort, study population is limited to: Newly diagnosed, morphologically documented AML, based on the World Health Organization (WHO) 2008 classification, with wild-type FLT3 and cytogenetics or mutations associated with intermediate or adverse prognostic risk per European Leukemia Net (ELN) guidelines. These include:
  • t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Show all 32Show fewer
  • Cytogenetic abnormalities not classified as favorable
  • t(6;9)(p23;q34.1); DEK-NUP214
  • t(v;11q23.3); KMT2A rearranged
  • t(9;22)(q34.1;q11.2); BCR-ABL1
  • inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
  • -5 or del(5q); -7; -17/abn(17p)
  • Complex karyotype - defined as three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring translocations or inversions, that is, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1
  • Monosomal karyotype - defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 additional monosomy or structural chromosome abnormality (excluding core-binding factor AML)
  • Mutated RUNX1 (without favorable risk cytogenetics/mutations)
  • Mutated BCOR (without favorable risk cytogenetics/mutations)
  • Mutated EZH2 (without favorable risk cytogenetics/mutations)
  • Mutated ASXL1 (without favorable risk cytogenetics/mutations)
  • Mutated SF3B1 (without favorable risk cytogenetics/mutations)
  • Mutated SRSF2 (without favorable risk cytogenetics/mutations)
  • Mutated STAG2 (without favorable risk cytogenetics/mutations)
  • Mutated U2AF1, (without favorable risk cytogenetics/mutations)
  • Mutated ZRSR2 (without favorable risk cytogenetics/mutations)
  • Mutated TP53 (mono- or biallelic) at a variant allele fraction of at least 10%
  • TREATMENT INCLUSION CRITERIA: Serum creatinine clearance >= 30 mL/min (as calculated by Cockcroft-Gault formula) (on or by day 8 of induction therapy, prior to starting pemigatinib)
  • TREATMENT INCLUSION CRITERIA: Serum phosphate within institutional upper limit of normal (ULN) or can be corrected with supplementation/ phosphate binders to be within institutional ULN (on or by day 8 of induction therapy, prior to starting pemigatinib)
  • TREATMENT INCLUSION CRITERIA: Serum electrolytes within institutional ULN: potassium, calcium (total, or corrected for serum albumin in case of hypoalbuminemia) and magnesium. If outside of normal limits, participant will be eligible when electrolytes are corrected (on or by day 8 of induction therapy, prior to starting pemigatinib)
  • TREATMENT INCLUSION CRITERIA: Total serum bilirubin =< 3 x ULN (on or by day 8 of induction therapy, prior to starting pemigatinib)
  • TREATMENT INCLUSION CRITERIA: Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 3 x ULN (on or by day 8 of induction therapy, prior to starting pemigatinib)
  • TREATMENT INCLUSION CRITERIA: Participants must consent to standard of care bone marrow aspirate/biopsies during treatment. Bone marrow biopsies will be obtained prior to study, on day 21 (+/- 3 days, if considered institutional standard of care), after recovery from induction therapy, and at the end of consolidation and/or prior to allogeneic stem cell transplant
  • TREATMENT INCLUSION CRITERIA: Female participants of childbearing potential must agree to use effective contraception (2 forms of contraception or abstinence) from the screening visit until 6 months following the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • TREATMENT INCLUSION CRITERIA: Male patients of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from the screening visit until 3 months following the last dose of study treatment. The male participant must also refrain from sperm donation from the screening visit until 3 months following the last dose of study treatment

Who cannot join

  • PRE-SCREENING EXCLUSION CRITERIA: Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype) per WHO classification
  • PRE-SCREENING EXCLUSION CRITERIA: AML with FLT3 mutations that qualify for standard of care treatment with 7+3 and midostaurin (e.g. FLT3 ITD or TKD with allelic ratio > 0.05)
  • PRE-SCREENING EXCLUSION CRITERIA: Favorable risk AML: inv(16), t(8;21), NPM1 mutations without FLT3-ITD, or in-frame mutations (mono- or biallelic) affecting the basic leucine zipper region of CEBPA
  • PRE-SCREENING EXCLUSION CRITERIA: Any cancer-directed therapy within 2 weeks prior to starting planned 7+3 induction regimen, with the exception of hydroxyurea, which is allowed to control white blood cell count, or empiric all-trans retinoic acid (ATRA) for suspected APL
  • PRE-SCREENING EXCLUSION CRITERIA: Prior receipt of a selective FGFR inhibitor
  • PRE-SCREENING EXCLUSION CRITERIA: Known liver disease
Show all 35Show fewer
  • PRE-SCREENING EXCLUSION CRITERIA: History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues
  • Except for commonly observed calcifications in soft tissues such as the skin, kidney tendon, or vessels due to injury, disease, or aging in the absence of systemic mineral imbalance)
  • PRE-SCREENING EXCLUSION CRITERIA: History of hypovitaminosis D being actively treated with supraphysiologic doses (e.g., 50,000 IU/weekly) to replenish the deficiency. Supraphysiologic doses of vitamin D need to be discontinued prior to starting pemigatinib. Vitamin D supplements are allowed
  • PRE-SCREENING EXCLUSION CRITERIA: Untreated human immunodeficiency virus (HIV) or active hepatitis C detectable by PCR, or chronic hepatitis B
  • Individuals positive for hepatitis B core antibody who are receiving intravenous immunoglobulin (IVIg) are eligible if HepB PCR is negative
  • PRE-SCREENING EXCLUSION CRITERIA: History of cerebrovascular accident or intracranial hemorrhage within 2 months of enrollment
  • PRE-SCREENING EXCLUSION CRITERIA: Unwillingness to receive infusion of blood products
  • PRE-SCREENING EXCLUSION CRITERIA: Inability to take oral medication
  • PRE-SCREENING EXCLUSION CRITERIA: Gastrointestinal condition/disorders that may raise gastric and/or small intestinal pH that could interfere with absorption, metabolism, or excretion of pemigatinib
  • PRE-SCREENING EXCLUSION CRITERIA: Known history and/or current evidence of ectopic mineralization/calcification, including (but not limited to): soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification
  • PRE-SCREENING EXCLUSION CRITERIA: Concurrent active malignancy with expected survival of < 1 year
  • PRE-SCREENING EXCLUSION CRITERIA: Active central nervous system involvement with AML
  • TREATMENT EXCLUSION CRITERIA: Clinically significant coagulation abnormality (e.g., disseminated intravascular coagulation) that is present on or by day 8 of induction therapy prior to starting pemigatinib
  • TREATMENT EXCLUSION CRITERIA: Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from day 1 of planned induction therapy, New York Heart Association class III or IV congestive heart failure, and uncontrolled arrhythmia (participants with pacemaker or with atrial fibrillation and well controlled heart rate are allowed). History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful.
  • A screening QT interval by Fridericia's Correction Formula (QTcF) interval > 480 ms will result in exclusion.
  • For participants with an intraventricular conduction delay (QRS interval > 120 ms), the JTc interval may be used in place of the QTc with approval from Sponsor-Investigator. The JTc must be =< 340 ms if JTc is used in place of the QTc.
  • TREATMENT EXCLUSION CRITERIA: Left ventricular ejection fraction (LVEF) by echocardiogram < 45% prior to initiating pemigatinib
  • TREATMENT EXCLUSION CRITERIA: Active infection that is not well-controlled by antibacterial or antiviral therapy
  • TREATMENT EXCLUSION CRITERIA: Current use of prohibited medications including use of any potent CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug.
  • Use of CYP3A4 inhibitors should be avoided but, if medically necessary, is permitted with a dose reduction of study drug
  • Use of moderate CYP3A4 inhibitors are permitted.
  • Based on the low overall bioavailability of topical ketoconazole, there are no restrictions on topical ketoconazole
  • TREATMENT EXCLUSION CRITERIA: Current use of prohibited medication
  • TREATMENT EXCLUSION CRITERIA: Hypersensitivity to pemigatinib, or its excipients, when administered alone
  • TREATMENT EXCLUSION CRITERIA: Current evidence of corneal disorder/keratopathy, including (but not limited to): bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis, etc., as confirmed by ophthalmologic examination.
  • TREATMENT EXCLUSION CRITERIA: Pregnancy or breastfeeding at the time of enrollment
  • TREATMENT EXCLUSION CRITERIA: Any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the participant or compliance with the protocol
  • TREATMENT EXCLUSION CRITERIA: Active central nervous system involvement with AML
  • TREATMENT EXCLUSION CRITERIA: Patients with FLT mutations

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

OHSU Knight Cancer Institute Clinical Trials Information contact

503-494-1080

trials@ohsu.edu

United States2 sites, 2 recruiting

  • UT Southwestern/Simmons Cancer Center-Dallas

    Dallas, Texas, 75390

    Yazan Madanat, MD, Yazan.Madanat@UTSouthwestern.edu

    Yazan Madanat, MD

    Recruiting

  • OHSU Knight Cancer Institute

    Portland, Oregon, 97239

    Elie Traer, MD PhD, 503-494-3553, traere@ohsu.edu

    Elie Traer, MD PhD

    Recruiting

Other trials in United States

About this study

Official title: A Multicenter, Phase 1, Open-Label Study of the FGFR Inhibitor Pemigatinib (INCB054828) Administered After Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML) With Adverse or Intermediate Risk Cytogenetics

This phase I trial identifies the best dose and clinical benefit of giving pemigatinib following standard induction chemotherapy in patients with newly diagnosed acute myeloid leukemia. Pemigatinib selectively inhibits FGFR (fibroblast growth factor receptor) activity, a receptor that may contribute to the growth of leukemia cells. The genetic changes responsible for activating the growth of leukemia cells can be unique to each patient and can change during the course of the disease. Chemotherapy drugs, such as cytarabine and daunorubicin work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To determine the maximum tolerated dose of pemigatinib (INC054828) following standard of care induction chemotherapy.

SECONDARY OBJECTIVES:

  1. To assess preliminary efficacy associated with study intervention. II. To assess the safety profile of the study intervention. III. To evaluate time-to- marrow recovery between cycles of pemigatinib.

EXPLORATORY OBJECTIVES:

  1. Assess minimal residual disease (MRD) by fluorescent in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and/or next-generation sequencing of acute myeloid leukemia (AML) genetic abnormalities in bone marrow and blood.

II. Quantify FGF2/FGFR immunohistochemical staining of marrow core biopsies and compare to historical controls at various timepoints.

III. Assess ex vivo sensitivity of patient-derived mononuclear cells to pemigatinib with and without FGF2 supplementation.

IV. Evaluate pemigatinib-induced changes in stromal expression using cultured bone marrow samples and compare to historical controls.

  1. Evaluate the impact of pemigatinib on the need for intravenous (IV) phosphate replacement after chemotherapy.

OUTLINE: This is a dose-escalation study of pemigatinib followed by a dose-expansion study.

INDUCTION: Patients receive cytarabine IV on days 1-7, daunorubicin IV on days 1-3, and pemigatinib orally (PO) once daily (QD) on days 8-21 in the absence of disease progression or unacceptable toxicity. Patients with hematologic count recovery (assessed between days 25-42) after induction proceed to consolidation therapy. Patients undergo echocardiography (ECHO) during screening and as clinically indicated on study. Patients undergo blood sample collection and bone marrow aspirate and biopsy during screening and cycle 11 day 21 on study.

CONSOLIDATION: Patients receive high dose cytarabine IV twice daily (BID) on days 1, 3, and 5 of each cycle, and pemigatinib PO QD on days 8-21 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression of unacceptable toxicity. Patients undergo ECHO as clinically indicated and blood sample collection and bone marrow biopsy and aspirate at the end of consolidation.

After completion of study treatment, patients are followed up every 3 months for up to 24 months.

Being tested
Biospecimen Collection, Bone Marrow Aspirate, Bone Marrow Biopsy, Cytarabine, Daunorubicin
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection

    Undergo blood sample collection

  • Bone Marrow AspirateProcedure or surgery

    Also called BONE MARROW, LIQUID, Human Bone Marrow Aspirate

    Undergo bone marrow biopsy and aspirate

  • Bone Marrow BiopsyProcedure or surgery

    Also called Biopsy of Bone Marrow, Biopsy, Bone Marrow

    Undergo bone marrow biopsy and aspiratie

  • CytarabineDrug

    Also called .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone

    Given IV

  • DaunorubicinDrug

    Also called Daunomycin, Daunorrubicina, DNR, Leukaemomycin C

    Given IV

  • ElectrocardiographyProcedure or surgery

    Also called ECG, EKG

    Undergo ECHO

  • PemigatinibDrug

    Also called INCB054828, Pemazyre

    Given PO

Study groups in NCT04659616
Study groupRoleWhat they receive
Treatment (cytarabine, daunorubicin, pemigatinib)ExperimentalINDUCTION: Patients receive cytarabine IV on days 1-7, daunorubicin IV on days 1-3, and pemigatinib PO QD on days 8-21 in the absence of disease progression or unacceptable toxicity. Patients with hematologic count recovery (assessed between days 25-42) after induction proceed to consolidation therapy. Patients undergo ECHO during screening and as clinically indicated on study. Patients undergo blood sample collection and bone marrow aspirate and biopsy during screening and cycle 11 day 21 on study. CONSOLIDATION: Patients receive high dose cytarabine IV BID on days 1, 3, and 5 of each cycle, and pemigatinib PO QD on days 8-21 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression of unacceptable toxicity. Patients undergo ECHO as clinically indicated and blood sample collection and bone marrow biopsy and aspirate at the end of consolidation.
Receives: Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspirate; Procedure: Bone Marrow Biopsy; Drug: Cytarabine; Drug: Daunorubicin; Procedure: Electrocardiography; Drug: Pemigatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of dose limiting toxicities (DLTs)

    Will be summarized using the proportion and exact binomial confidence interval. DLTs will be summarized at each dose level by severity and major organ site according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

    Measured: From cycle 1 day 8, until 14 days after cycle 1 day 28 (up to 42 days)

Secondary outcomes (8)

  1. Rate of composite complete remission (cCR)

    Measured: From cycle 1 day 1, until blood cell count recovery after induction (day 25-42)

  2. Duration of remission (DOR)

    Measured: Date of first response (>= immune complete remission) till date of documented relapse assessed up to 2 years from last dose of study intervention

  3. Event-free survival (EFS)

    Measured: From cycle 1 day 1, until date of primary refractory disease, progression, relapse, or death from any cause, assessed up to 2 years from last dose of study intervention

  4. Relapse-free survival (RFS)

    Measured: Date of first response (>= complete remission with incomplete blood count recovery [CRi]), until date of relapse or death from any cause, assessed up to 2 years from last dose of study intervention

  5. Overall survival (OS)

    Estimated with the Kaplan-Meier method.

    Measured: From cycle 1 day 1, until date of death from any cause, assessed up to 2 years from last dose of study intervention

  6. Incidence of treatment-emergent adverse events (TEAEs)

    Will be determined for the safety analysis set (i.e., study participants who receive at least one dose of pemigatinib) and the subset of safety evaluable patients treated at the MTD. The point estimate and 95% confidence interval will be reported. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v5.0. Will be evaluated in the dose determining and dose expansion cohorts separately as well as combined.

    Measured: From cycle 1 day 8, until 90 days after last dose of study intervention

  7. Incidence of non-treatment related adverse events (AEs)

    Will be determined for the safety analysis set (i.e., study participants who receive at least one dose of pemigatinib) and the subset of safety evaluable patients treated at the MTD. The point estimate and 95% confidence interval will be reported. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v5.0. Will be evaluated in the dose determining and dose expansion cohorts separately as well as combined

    Measured: From cycle 1 day 8, until 90 days after last dose of study intervention

  8. Time-to-marrow recovery

    Defined as absolute neutrophil count (ANC) >= 1 x 10^9 /L and platelets >= 100 x 10^9/L.

    Measured: Baseline (cycle 1 day 1), until time of count recovery

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Dec 2020
  2. Study start14 Jan 2021
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
32 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04659616
Sponsor's protocol ID
STUDY00020009
Other IDs
NCI-2020-05267, STUDY00020009
Status last verified
Jul 2026
First submitted
20 Aug 2020
Last updated
14 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Al-Bazaz M, Forstreuter A, Hammada I, Hille J, Wagner JN, Reinert J, Wehrhahn J, Bokemeyer C, Fiedler W. Acute Lymphoblastic Leukemia Characterized by Rare BCR::FGFR1 Translocation: A Case Report With Literature Review. Case Rep Hematol. 2025 Oct 23;2025:8892036. doi: 10.1155/crh/8892036. eCollection 2025.

    PubMed 41180818

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Biospecimen Collection, Bone Marrow Aspirate and Bone Marrow Biopsy in people with Acute Myeloid Leukemia, run by OHSU Knight Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 14 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact OHSU Knight Cancer Institute Clinical Trials Information (503-494-1080, trials@ohsu.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of dose limiting toxicities (DLTs) (time frame: From cycle 1 day 8, until 14 days after cycle 1 day 28 (up to 42 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04659616, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2026.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in