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NCT05176483PHASE1Recruiting

Study of Zanzalintinib in Combination With Immuno-Oncology Agents in Participants With Solid Tumors

Exelixis

Start Date

12/14/2021

Completion Date

6/28/2030

Summary

This is a multicenter Phase 1b, open label, dose-escalation and cohort-expansion study, evaluating the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity, and effect of biomarkers of zanzalintinib administered alone, and in combination with nivolumab (doublet), nivolumab + ipilimumab (triplet) and nivolumab + relatlimab (triplet) in participants with advanced solid tumors. In the Expansion Stage, the safety and efficacy of zanzalintinib as monotherapy and in combination therapy will be further evaluated in tumor-specific Expansion Cohorts.

Eligibility Criteria

Age Range: 18 years to No maximum

Key Inclusion Criteria: * Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic. * Dose-Escalation Cohorts: Participants with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective. * Expansion Cohort 1 (ccRCC): Participants with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy. * Note: Prior non-vascular endothelial growth factor (VEGF) targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose. * Expansion Cohort 2 (ccRCC): Participants with unresectable advanced or metastatic RCC with a clear cell component. * Must have radiographically progressed after a combination therapy consisting of a Programmed Cell Death Protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) targeting monoclonal antibody (mAb) with a Vascular endothelial growth factor (receptor) tyrosine kinase inhibitor (VEGFR-TKI) or a PD-1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy. * Must have received no more than one prior systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma. * Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate. * Must have progressed during or after one novel hormone therapy (NHT) given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC. * Expansion Cohort 4 (UC, ICI-naive): Participants with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra). * Must have progressed during or after prior first-line platinum-based combination therapy, including participants who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence \< 12 months from the end of last therapy. * Must have received no more than 1 prior line of systemic anticancer therapy for unresectable, locally advanced or metastatic disease. * Expansion Cohort 5 (post enfortumab vedotin \[EV\] and ICI): Participants with histologically confirmed unresectable, locally advanced or metastatic predominant urothelial carcinoma. * Progressive disease following prior EV or ineligible for EV, and progression following prior PD-1/PD-L1 inhibitor or ineligible for PD-1/PD-L1 inhibitor. * Prior receipt of platinum-based therapy allowed but not required. * Prior therapy with other agents allowed but not required. * Expansion Cohort 6 (nccRCC): Participants with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary, unclassified RCC, and translocation-associated, Fumarate Hydratase (FH) deficient and Succinate Dehydrogenase (SDH) deficient. Among the eligible histologic subtypes, sarcomatoid features are allowed. * No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant therapy if disease recurrence occurred at least 6 months after the last dose. * Expansion Cohort 7 (HCC): Participants with locally advanced, or metastatic and/or unresectable HCC that is not amenable to curative treatment or locoregional therapy. * Expansion Cohort 8 (NSCLC): Participants with Stage IV non-squamous NSCLC with positive PD-L1 expression (tumor proportion score \[TPS\] 1-49%) and without prior systemic anticancer therapy for metastatic disease. * Expansion Cohort 9 (NSCLC): Participants with Stage IV non-squamous NSCLC who have radiologically progressed following treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease. * Expansion Cohort 10 (CRC): Participants with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum. * Expansion Cohort 11 (HNSCC): Participant with inoperable, refractory, recurrent or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1 combined positive score (CPS) ≥1. * Expansion Cohort 12 (ccRCC): Participants with unresectable advance or metastatic RCC with a clear cell component, including participants who also have a sacromatoid feature. * Must have received no more than two prior lines of systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma * Expansion Cohort 13 and Cohort 14 (ccRCC 1L): Participants with unresectable advanced or metastatic RCC with a clear component, including participants who also have a sacromatoid feature. * For all Expansion Cohorts except Cohort 3: Measurable disease per RECIST 1.1 as determined by the Investigator. * For Expansion Cohorts 1 - 11 Only: Archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained. * Recovery to baseline or ≤ Grade 1 common terminology criteria for adverse events (CTCAE) v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy. * Karnofsky Performance Status (KPS) ≥ 70%. * Adequate organ and marrow function. * Sexually active fertile participants and their partners must agree to use highly effective methods of contraception. * Females of childbearing potential must not be pregnant at screening. Key Exclusion Criteria: * For all Dose-Escalation cohorts: Prior treatment with zanzalintinib. For all Expansion Cohorts: Prior treatment with zanzalintinib, nivolumab, ipilimumab or relatlimab with the following exceptions: Prior PD-1/PD-L1, Lymphocyte-activation gene 3 (LAG-3) and cCytotoxic T lymphocyte associated protein 4 (CTLA-4) targeting therapy for locally advanced or metastatic disease is allowed for Cohort 2 (ccRCC), Cohort 5 (UC), Cohort 9 (NSCLC), and Cohort 12 (ccRCC), and prior treatment in the neoadjuvant or adjuvant setting is allowed for Cohort 13 and Cohort 14 (ccRCC 1L). * For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC), Cohort 10 (CRC), and Cohort 12: Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment. * For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment. * For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), Cohort 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC) and Cohort 10 (CRC), and Cohort 12: Receipt of any type of anticancer antibody or systemic chemotherapy within 4 weeks before first dose of study treatment. * Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment. * Prior external radiation therapy for bone metastasis within 2 weeks, for other tumor sites within 4 weeks, and prior radium-223 therapy within 6 weeks before first dose of study treatment, unless otherwise specified. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. * Concomitant anticoagulation with oral anticoagulants, except for specified direct factor Xa inhibitors. * Administration of a live, attenuated vaccine within 30 days prior to first dose. * Uncontrolled, significant intercurrent or recent illness. * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 460 ms for females and \> 450 ms for males per electrocardiogram (ECG) within 14 days before first dose of study treatment. * Participants with inadequately treated adrenal insufficiency. * Pregnant or lactating females. * Any other active malignancy within two years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6. * For Cohort 2 (ccRCC, 2L): Receipt of a prior triplet therapy including a VEGFR-TKI, a PD1 targeting mAb, and a CTLA-4 mAb. * For Cohort 3 (mCRPC): Receipt of a taxane-based chemotherapy for mCRPC. * For Cohort 4 (UC, ICI-naïve): Participants who have had recurrence within the 6 months of completing adjuvant anti-PD-(L)1 treatment. * For Cohort 6 (nccRCC, 1L): Participants with chromophobe, renal medullary carcinoma, or pure collecting duct nccRCC. * For Cohort 7 (HCC): * Documented hepatic encephalopathy (HE) within 6 months before the first dose. * Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) within 6 months before randomization. * Participants who have received any local anticancer therapy including surgery, percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) within 28 days prior to first dose. * Participants with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma * For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/or trifluridine + tipiracil (TAS-102). * For Cohort 11 (HNSCC): Primary tumor site of the nasopharyngeal area. * For Cohorts 1 (ccRCC, 1L), 2 (ccRCC, 2L), 4, 5 (UC), 7 (HCC), 8 (NSCLC 1L PD-L1 low), 9 (NSCLC, 2L+), 10 (CRC, microsatellite stable \[MSS\], 2L+), and 11 (HNSCC): * Troponin T (TnT) or I (TnI) \> 2 × institutional upper limit of normal (ULN). Note: Additional Inclusion and Exclusion criteria may apply.

Interventions

DRUG

Zanzalintinib

DRUG

Nivolumab

DRUG

Ipilimumab

DRUG

Nivolumab

DRUG

Nivolumab

DRUG

Nivolumab + Relatlimab

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Conditions

Renal Cell Carcinoma (RCC)Metastatic Castration-Resistant Prostate Cancer (mCRPC)Urothelial Carcinoma (UC)Solid TumorHepatocellular Carcinoma (HCC)Non-small Cell Lung Cancer (NSCLC)Colorectal Cancer (CRC)Head and Neck Squamous Cell Carcinoma (HNSCC)Clear Cell Renal Cell Carcinoma (ccRCC)Non-Clear Cell Renal Cell Carcinoma (nccRCC)

Locations

Exelixis Clinical Site #67

Phoenix, Arizona 85054

United States

Exelixis Clinical Site #1

Tucson, Arizona 85711

United States

Exelixis Clinical Site #123

Palo Alto, California 94304

United States

Exelixis Clinical Site #59

Santa Barbara, California 93463

United States

Exelixis Clinical Site #87

Littleton, Colorado 80124

United States

Exelixis Clinical Site #62

New Haven, Connecticut 06510

United States

Exelixis Clinical Site #49

Newark, Delaware 19713

United States

Exelixis Clinical Site #48

Celebration, Florida 34747

United States

Exelixis Clinical Site #11

Gainesville, Florida 32610

United States

Exelixis Clinical Site #78

Jacksonville, Florida 32224

United States

Exelixis Clinical Site #47

Miami, Florida 33136

United States

Exelixis Clinical Site #61

Plantation, Florida 33322

United States

Exelixis Clinical Site #8

Tampa, Florida 33612

United States

Exelixis Clinical Site #26

Chicago, Illinois 60612

United States

Exelixis Clinical Site #4

Indianapolis, Indiana 46250

United States

Exelixis Clinical Site #122

Louisville, Kentucky 40202

United States

Exelixis Clinical Site #14

Baltimore, Maryland 21201

United States

Exelixis Clinical Site #7

Boston, Massachusetts 02215

United States

Exelixis Clinical Site #65

Detroit, Michigan 48201

United States

Exelixis Clinical Site #13

Detroit, Michigan 48202

United States

Exelixis Clinical Site #68

Rochester, Minnesota 55905

United States

Exelixis Clinical Site #2

Omaha, Nebraska 68130

United States

Exelixis Clinical Site #5

Omaha, Nebraska 68130

United States

Exelixis Clinical Site #55

Las Vegas, Nevada 89052

United States

Exelixis Clinical Site #88

East Brunswick, New Jersey 08816

United States

Exelixis Clinical Site #105

Hackensack, New Jersey 07601

United States

Exelixis Clinical Site #60

New York, New York 10032

United States

Exelixis Clinical Site #6

New York, New York 10065

United States

Exelixis Clinical Site #76

Syracuse, New York 13210

United States

Exelixis Clinical Site #12

Durham, North Carolina 27710

United States

Exelixis Clinical Site #10

Cleveland, Ohio 44106

United States

Exelixis Clinical Site #51

Portland, Oregon 97239

United States

Exelixis Clinical Site #104

Hershey, Pennsylvania 17033

United States

Exelixis Clinical Site #98

Philadelphia, Pennsylvania 19104

United States

Exelixis Clinical Site #32

Pittsburgh, Pennsylvania 15212

United States

Exelixis Clinical Site #24

Pittsburgh, Pennsylvania 15232

United States

Exelixis Clinical Site #9

Myrtle Beach, South Carolina 29572

United States

Exelixis Clinical Site #3

Nashville, Tennessee 37203

United States

Exelixis Clinical Site #46

Austin, Texas 78705

United States

Exelixis Clinical Site #111

Dallas, Texas 75246

United States

Exelixis Clinical Site #89

Dallas, Texas 75246

United States

Exelixis Clinical Site #73

Irving, Texas 75063

United States

Exelixis Clinical Site #50

Plano, Texas 75075

United States

Exelixis Clinical Site #70

Tyler, Texas 75601

United States

Exelixis Clinical Site #66

Charlottesville, Virginia 22903

United States

Exelixis Clinical Site #33

Milwaukee, Wisconsin 53226

United States

Exelixis Clinical Site #116

Albury, 2640

Australia

Exelixis Clinical Site #35

Birtinya, 4575

Australia

Exelixis Clinical Site #16

Brisbane, 4102

Australia

Exelixis Clinical Site #42

Saint Leonards, 2065

Australia

Exelixis Clinical Site #36

Sydney, 2109

Australia

Exelixis Clinical Site #94

Graz, 8036

Austria

Exelixis Clinical Site #31

Salzburg, 5020

Austria

Exelixis Clinical Site #29

Vienna, 1020

Austria

Exelixis Clinical Site #106

Wein, 1090

Austria

Exelixis Clinical Site #39

Anderlecht, 1070

Belgium

Exelixis Clinical Site #37

Kortrijk, 8500

Belgium

Exelixis Clinical Site #85

Besançon, 25030

France

Exelixis Clinical Site #96

Bordeaux, 33000

France

Exelixis Clinical Site #79

Caen, 14076

France

Exelixis Clinical Site #118

Clermont-Ferrand, 63011

France

Exelixis Clinical Site #109

Lyon, 69008

France

Exelixis Clinical Site #92

Marseille, 13273

France

Exelixis Clinical Site #64

Nice, 06189

France

Exelixis Clinical Site #83

Paris, 75010

France

Exelixis Clinical Site #91

Paris, 75015

France

Exelixis Clinical Site #80

Rennes, 35042

France

Exelixis Clinical Site #63

Saint-Herblain, 44805

France

Exelixis Clinical Site #75

Strasbourg, 67200

France

Exelixis Clinical Site #84

Vandœuvre-lès-Nancy, 54519

France

Exelixis Clinical Site #115

Villejuif, 94805

France

Exelixis Clinical Site #103

Essen, 45147

Germany

Exelixis Clinical Site #113

Hamburg, 22763

Germany

Exelixis Clinical Site #108

Heidelberg, 69120

Germany

Exelixis Clinical Site #82

Herne, 44625

Germany

Exelixis Clinical Site #93

Jena, 07747

Germany

Exelixis Clinical Site #112

München, 81737

Germany

Exelixis Clinical Site #102

Nürtingen, 72622

Germany

Exelixis Clinical Site #107

Trier, 54292

Germany

Exelixis Clinical Site #95

Tübingen, 72076

Germany

Exelixis Clinical Site #86

Beersheba, 8410101

Israel

Exelixis Clinical Site #72

Haifa, 3109601

Israel

Exelixis Clinical Site #52

Jerusalem, 9112001

Israel

Exelixis Clinical Site #71

Petah Tikva, 4941492

Israel

Exelixis Clinical Site #69

Tel Aviv, 6423906

Israel

Exelixis Clinical Site #38

Ẕerifin, 7030000

Israel

Exelixis Clinical Site #121

Ancona, 60020

Italy

Exelixis Clinical Site #117

Bologna, 40138

Italy

Exelixis Clinical Site #90

Florence, 50134

Italy

Exelixis Clinical Site #101

Milan, 20132

Italy

Exelixis Clinical Site #81

Milan, 20141

Italy

Exelixis Clinical Site #40

Naples, 80131

Italy

Exelixis Clinical Site #74

Ravenna, 48121

Italy

Exelixis Clinical Site #30

Grafton, 1023

New Zealand

Exelixis Clinical Site #45

Hamilton, 3204

New Zealand

Exelixis Clinical Site #20

Bydgoszcz, 85-796

Poland

Exelixis Clinical Site #28

Gdansk, 80-219

Poland

Exelixis Clinical Site #34

Otwock, 05-400

Poland

Exelixis Clinical Site #54

Poznan, 60-569

Poland

Exelixis Clinical Site #114

Wroclaw, 53-413

Poland

Exelixis Clinical Site #41

Badajoz, 06080

Spain

Exelixis Clinical Site #53

Barcelona, 08035

Spain

Exelixis Clinical Site #15

Barcelona, 08036

Spain

Exelixis Clinical Site #27

Barcelona, 08041

Spain

Exelixis Clinical Site #120

L'Hospitalet de Llobregat, 08908

Spain

Exelixis Clinical Site #57

Madrid, 28033

Spain

Exelixis Clinical Site #43

Madrid, 28034

Spain

Exelixis Clinical Site #58

Madrid, 28040

Spain

Exelixis Clinical Site #77

Madrid, 28040

Spain

Exelixis Clinical Site #19

Madrid, 28041

Spain

Exelixis Clinical Site #100

Madrid, 28046

Spain

Exelixis Clinical Site #18

Pamplona, 31008

Spain

Exelixis Clinical Site #119

Santander, 39008

Spain

Exelixis Clinical Site #23

Seville, 41013

Spain

Exelixis Clinical Site #56

Valencia, 46010

Spain

Exelixis Clinical Site #25

Valencia, 46026

Spain

Exelixis Clinical Site #21

Chur, 7000

Switzerland

Exelixis Clinical Site #22

Sankt Gallen, 9007

Switzerland

Exelixis Clinical Site #44

Winterthur, 8401

Switzerland

Exelixis Clinical Site #110

Cambridge, CB2 0QQ

United Kingdom

Exelixis Clinical Site #99

London, W6 8RF

United Kingdom

Exelixis Clinical Site #97

Middlesex, HA6 2RN

United Kingdom