This Study in Patients With Different Types of Cancer (Solid Tumours) Aims to Find a Safe Dose of Xentuzumab in Combination With Abemaciclib With or Without Hormonal Therapies. The Study Also Tests How Effective These Medicines Are in Patients With Lung and Breast Cancer

Inclusion Criteria

All Cohorts

* Age ≥ 18 years (≥20 years for Japan only) at screening
* Signed and dated written informed consent in accordance with GCP (Good Clinical Practice ) and local legislation prior to admission to the trial
* WHO/ECOG (World Health Organization / Eastern Cooperative Oncology Group) performance status 0-1 assessed at screening
* Patient must be able to swallow oral capsules or tablets

Cohort A (Solid Tumours) \& Cohort E (NSCLC):

\- Male or female patients ready and able to use highly effective methods of birth control during the study and for 3 weeks following the last dose of abemaciclib per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Women of childbearing potential must have a negative serum pregnancy test at screening.

Cohort A (Solid Tumours)

* Patients with histologically or cytologically confirmed diagnosis of advanced and/or metastatic, measurable or evaluable, non-resectable solid tumours
* Patients must have received and failed, or have been intolerant to, all treatment known to confer clinical benefit or have no therapeutic options available as deemed appropriate by their treating physician
* Life expectancy ≥ 3 months in the opinion of the investigator assessed at screening;

Cohorts B, C, D (dose finding, Breast Cancer) \& Cohort D1 and Cohort D2 (Breast Cancer):

* Women who have postmenopausal status due to either surgical/natural menopause or chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or radiation-induced ovarian suppression.

  \-- postmenopausal status due to surgical/natural menopause requires at least one of the following conditions:
* prior bilateral oophorectomy
* age ≥ 60 years
* age \< 60 years and amenorrheic (in the absence of tamoxifen, toremifene, ovarian suppression, or chemotherapy) for at least 12 months; and follicle-stimulating hormone (FSH) and estradiol within the postmenopausal range as per institutional reference ranges.
* Postmenopausal status due to radiation-induced ovarian suppression must be confirmed by FSH and estradiol level in the postmenopausal range.
* Histologically or cytologically proven diagnosis of breast cancer with evidence of locally advanced disease not amenable to curative resection or metastatic disease
* HR+ (local lab results at screening or, if not available, at the time of diagnosis) To fulfil the requirement of HR+ disease, the primary tumour or metastatic lesion of the breast cancer must express at least one of the hormone receptors (estrogen receptor \[ER\] or progesterone receptor \[PgR\]) by immunohistochemistry (IHC). Estrogen receptor and PgR assays are considered positive if there are at least 1% positive tumour nuclei in the sample as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).
* HER2 negative (local lab results at screening or, if not available, at the time of diagnosis) as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).

Cohorts B, C, D (dose finding), F (Breast Cancer):

* Previous adjuvant and neoadjuvant chemotherapy is permitted. 0-2 prior lines of chemotherapy for the metastatic setting are allowed (except Cohorts D1, D2 and F).
* At least 1 lesion (measurable or non-measurable) that can be accurately assessed at baseline with CT or MRI or PET-CT (CT portion of diagnostic quality) and which is suitable for accurate repeated measurement.
* Cohort B, C, D: Must be eligible for the corresponding hormonal therapy (letrozole, anastrozole or fulvestrant). For Cohorts B and C previous treatment with fulvestrant or exemestane is allowed. For For Cohort D, prior therapy with non steroidal aromatase inhibitors (anastrozole, letrozole) or exemestane are permitted.

Cohort E (NSCLC (Non-Small Cell Lung Cancer)):

* Histologically or cytologically confirmed diagnosis of stage IV NSCLC.
* The participant must have progressed after platinum-based chemotherapy AND immunotherapy (unless deemed inappropriate candidates for immunotherapy by their treating physician) AND have received 1 or a maximum of 2 other prior chemotherapy for advanced and/or metastatic disease OR must be judged by the physician as ineligible for further standard second-line chemotherapy. Prior treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anaplastic lymphoma kinase (ALK) inhibitors is mandatory in participants whose tumour has EGFR-activating mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant therapies are permitted.
* Have adequate organ function including haematology, renal, and liver.
* Have measureable disease per RECIST 1.1.

Cohort D1, Cohort D2 and Cohort F (Breast Cancer):

* Have a negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 3 weeks following the last dose of abemaciclib and for at least 6 months after last dose of xentuzumab if postmenopausal status is due to ovarian suppression with a GnRH agonist.
* Have either measurable disease or non-measurable bone only disease. Measurable and non-measurable diseases are defined according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1 \[v1.1\]. Non-measurable bone only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft tissue component, or mixed lytic-blastic bone lesions without a measurable soft tissue component.

Cohort D1 and D2 only:

* Patients must fulfil 1 of the following criteria:

  \-- Relapsed with radiologic evidence of progression while receiving neoadjuvant or adjuvant endocrine therapy, with no subsequent endocrine therapy received following progression.
* Relapsed with radiologic evidence of progression within 1 year from completion of adjuvant endocrine therapy, with no subsequent endocrine therapy received following progression.
* Relapsed with radiologic evidence of progression more than 1 year from completion of adjuvant endocrine therapy and then subsequently relapsed with radiologic evidence of progression after receiving treatment with either an anti-estrogen or an aromatase inhibitor as first-line endocrine therapy for metastatic disease. Patients may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic disease.
* Presented de novo with metastatic disease and then relapsed with radiologic evidence of progression after receiving treatment with either an anti-estrogen or an aromatase inhibitor as first-line endocrine therapy for metastatic disease.

Patients may not have received more than 1 line of endocrine therapy or any prior chemotherapy for metastatic disease.

\- For cohort D1 (visceral disease) patient must have at least one documented visceral metastasis; for cohort D2 (non-visceral disease), patient must not have any visceral metastasis.

Cohort F only:

* Patients with resistance to prior therapy with an aromatase inhibitor (AI) and CDK4/6 inhibitor (excluding abemaciclib) for locally advanced or metastatic breast cancer, defined as radiologic evidence of disease progression while on, or within 30 days after last dose of AI and/or CDK4/6 inhibitor (excl. abemaciclib) administered as first-line therapy for locally advanced or metastatic disease. Patients may not have received more than 1 line of prior endocrine based therapy or any prior chemotherapy for advanced/metastatic disease.
* Patient must not have any visceral metastasis (example of allowed lesions are in breast, lymph nodes, soft tissue, bone).

Exclusion criteria

All - Cohorts A, B, C, D (dose finding), E and F \& Cohort D1 and Cohort D2 (Breast Cancer):

* Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial
* Previous treatment in this trial
* Currently enrolled in another investigational device or drug study, or less than 21 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s).
* Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes them an unreliable study subject or unlikely to complete the trial
* Prior anti-cancer chemotherapy, biological or radiation therapy, androgens, thalidomide, other anticancer agents, or any investigational drug within 21 days (14 days for non-myelosuppressive agents); and/or 4 weeks for immunotherapy, before starting any of the trial drugs.
* Prior radiotherapy to ≥ 25% of bone marrow regardless of when it was received
* Unresolved treatment related toxicity from previous therapy of \> CTCAE grade 1 at study entry (except for stable sensory neuropathy ≤ CTCAE grade 2 and alopecia)
* Previous treatment with IGF-1R targeting compounds
* The patient has serious and/or uncontrolled pre-existing medical condition(s) that, in the judgement of the Investigator, would preclude participation in this study, including interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy.
* Inadequate bone marrow reserve or organ function as demonstrated by any of the following: ANC \< 1.5 x 10\^9/L, platelets \< 100 x 10\^9/L, haemoglobin \<90g/L, ALT \> 2.5 x ULN or \> 5 x ULN in the presence of liver metastases, total bilirubin \>1.5 x ULN or \>3 x ULN in patients with Gilbert's syndrome, serum creatinine \> 1.5 x ULN concurrent with creatinine clearance ≤ 50 mL/min.
* Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis
* Refractory nausea and vomiting, chronic GI diseases, inability to swallow the product, or previous significant bowel resection that would preclude adequate absorption of abemaciclib or resulting in baseline Grade 2 or higher diarrhoea
* Patients with Diabetes Type I or uncontrolled Type II (defined by HgBA1C \> 8%).
* Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% of liver involvement in metastases.
* Prior hematopoietic stem cell or bone marrow transplant
* Have a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Subjects with controlled atrial fibrillation for \>30 days prior to study treatment are eligible.
* Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The primary prophylactic use of G-CSF is not permitted but it may be used to treat treatment emergent neutropenia.
* Have had major surgery (excluding biopsy) \< 28 days of the initial dose of any of the study drugs or planned major surgery during study participation.
* Have active bacterial or fungal infection (that is, requiring IV antibiotics or therapy at time of initiating study treatment), and/or known viral infection (for example, human immunodeficiency virus \[HIV\] antibodies, hepatitis B surface antigen, or hepatitis C antibodies). Screening is not required for enrolment.
* Patients with baseline Grade ≥2 hyperglycaemia or patients with baseline Grade ≥ 2 diarrhoea
* Patients needing treatment with CYP3A4 inhibitors/inducers cannot be included in the trial.

Cohorts A, B, C, D (dose finding), E and F

* Any documented active or suspected malignancy or history of malignancy, other than the disease under study, within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix or ductal carcinoma in situ (DCIS) if properly treated in opinion of the investigator.
* Women who are pregnant, nursing, or who plan to become pregnant while in the trial. Men who plan to father a child while in the trial.
* Prior anti CDK agents
* Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease, as indicated by clinical symptoms, cerebral oedema, and/or progressive growth. History of CNS metastases or cord compression are eligible if they have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are clinically stable, off anticonvulsants and steroids for at least 4 weeks. Patients with brain metastases are eligible if they are asymptomatic, completed radiotherapy for at least 4 weeks or are on a stable dose of steroids for at least 4 weeks. Patients are not eligible if they have spinal cord compression.
* History of hypersensitivity to active or inactive excipients of xentuzumab, abemaciclib or letrozole/anastrozole/fulvestrant, or loperamide hydrochloride, or drugs with similar chemical structures

Cohort D1, Cohort D2 and Cohort F (Breast Cancer):

* Any documented active or suspected malignancy or history of malignancy (including inflammatory breast cancer), other than the disease under study, within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix or ductal carcinoma in situ (DCIS) if properly treated in opinion of the investigator.
* Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
* Have received prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, everolimus, alpelisib or abemaciclib. For cohorts D1 and D2 only: prior treatment with palbociclib or ribociclib is also excluded)
* Have clinical evidence or history of central nervous system metastasis. Screening is not required for enrolment.
* History of hypersensitivity to active or inactive excipients of xentuzumab, abemaciclib or fulvestrant, or loperamide hydrochloride, or drugs with similar chemical structures
* Have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for example, denosumab) \<7 days prior to initiation of any study drug.
* Further exclusion criteria apply